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V 



FOOD AND DRUG ADMINISTRATION'S 
REGULATION OF DIETARY SUPPLEMENTS 



Y4.G 74/7: F 73/16 

Food and Drug Adninistration's Regu. . . ■ 

HEARING 

BEFORE THE 

HUMAN RESOURCES AND INTERGOVERNMENTAL 
RELATIONS SUBCOMMITTEE 

OF THE 

COMMITTEE ON 

GOVERNMENT OPERATIONS 

HOUSE OF REPRESENTATIVES 

ONE HUNDRED THIRD CONGRESS 

FIRST SESSION 



JULY 20, 1993 



Printed for the use of the Committee on Government Operations 





FOOD AND DRUG ADMINISTRATION'S 
REGULATION OF DIETARY SUPPLEMENTS 



HEARING 

BEFORE THE 

HUMAN RESOURCES AND INTERGOVERNMENTAL 
RELATIONS SUBCOMMITTEE 

OF THE 

COMMITTEE ON 

GOVERNMENT OPERATIONS 

HOUSE OF REPRESENTATIVES 

ONE HUNDRED THIRD CONGRESS 

FIRST SESSION 



JULY 20, 1993 



Printed for the use of the Committee on Government Operations 




U.S. GOVERNMENT PRINTING OFFICE 
84-512 CC WASHINGTON : 1994 

For sale by the U.S. Government Printing Office 
Superintendent of Documents, Congressional Sales Office, Washington, DC 20402 
ISBN 0-16-046431-5 



COMMITTEE ON GOVERNMENT OPERATIONS 



JOHN CONYERS, 
CARDISS COLLINS, Illinois 
GLENN ENGLISH, Oklahoma 
HENRY A. WAXMAN, California 
MIKE SYNAR, Oklahoma 
STEPHEN L. NEAL, North Carolina 
TOM LANTOS, California 
MAJOR R. OWENS, New York 
EDOLPHUS TOWNS, New York 
JOHN M. SPRATT, JR., South Carolina 
GARY A. CONDIT, California 
COLLIN C. PETERSON, Minnesota 
KAREN L. THURMAN, Florida 
BOBBY L. RUSH, Illinois 
CAROLYN B. MALONEY, New York 
THOMAS M. BARRETT, Wisconsin 
DONALD M. PAYNE, New Jersey 
FLOYD H. FLAKE, New York 
JAMES A. HAYES, Louisiana 
CRAIG A. WASHINGTON, Texas 
BARBARA-ROSE COLLINS, Michigan 
CORRINE BROWN, Florida 
MARJORIE MARGOLIES-MEZVINSKY, 

Pennsylvania 
LYNN C. WOOLSEY, California 



JR. 



Michigan, Chairman 

WILLIAM F. CLINGER, JR., Pennsylvania 
AL McCANDLESS, California 
J. DENNIS HASTERT, Illinois 
JON L. KYL, Arizona 
CHRISTOPHER SHAYS, Connecticut 
STEVEN SCHIFF, New Mexico 
CHRISTOPHER COX, California 
CRAIG THOMAS, Wyoming 
ILEANA ROS-LEHTINEN, Florida 
RONALD K. MACHTLEY, Rhode Island 
DICK ZIMMER, New Jersey 
WILLIAM H. ZELIFF, Jr., New Hampshire 
JOHN M. McHUGH, New York 
STEPHEN HORN, California 
DEBORAH PRYCE, Ohio 
JOHN L. MICA, Florida 
ROB PORTMAN, Ohio 



BERNARD SANDERS, Vermont 
(Independent) 



Julian Epstein, Staff Director 
Matthew R. FLETCHER, Minority Staff Director 



Human Resources and Intergovernmental Relations Subcommittee 

EDOLPHUS TOWNS, New York, Chairman 
HENRY A. WAXMAN, California STEVEN SCHIFF, New Mexico 

THOMAS M. BARRETT, Wisconsin STEPHEN HORN, California 

DONALD M. PAYNE, New Jersey JOHN L. MICA, Florida 

CRAIG A. WASHINGTON, Texas 

BERNARD SANDERS, Vermont (Ind.) 

Ex Officio 

JOHN CONYERS, JR., Michigan WILLIAM F. CLINGER, JR., Pennsylvania 

RONALD A. STROMAN, Staff Director 
William M. Layden, Professional Staff Member 
BRENDA E. PlLLORS, Professional Staff Member 

MARTINE M. DlCROCE, Clerk 
MARTHA B. MORGAN, Minority Professional Staff 



(II) 



CONTENTS 



Page 

Hearing held on July 20, 1993 1 

Statement of: 

Bailey, Lynn B., Ph.D., nutrition professor, Food Science and Human 
Nutrition Department, University of Florida 216 

Block, Gladys, Ph.D., University of California, Berkeley 186 

Cordaro, J.B., president, Council for Responsible Nutrition 128 

Hildwine, Regina, director, Technical Regulatory Affairs, National Food 

Processors Association, accompanied by John Bode, legislative counsel .. 172 

Huxtable, Ryan J., Ph.D., University of Arizona 238 

Johnston, Richard, M.D., senior vice president, programs, and medical 

director, March of Dimes Birth Defects Foundation 86 

McCaleb, Robert S., Herb Research Foundation 365 

McNamara, Stephen H., Hyman, Phelps & McNamara, P.C., on behalf 
of the Utah Natural Products Alliance 41 

Rosenberg, Irwin H., professor of medicine and nutrition, Tufts Univer- 
sity 210 

Shank, Fred R., Ph.D., Director, Center for Food Safety and Applied 
Nutrition [CFSAN], Food and Drug Administration, accompanied by 
Mitchell Zeller, Office of the Deputy Commissioner for Policy; Robert 
Lake, Director, Office of Policy, Planning and Strategic Initiatives; 
and Lori Love, Ph.D., Director, Clinical Research and Review Staff 4 

Silverglade, Bruce, director, legal affairs, Center for Science in the Public 

Interest 64 

Stark, Shirley, assistant attorney general of New York 103 

Sternberg, Esther M., M.D., Chief, Unit on Neuroendocrine Immunology 
and Behavior, Clinical Neuroendocrinology Branch, National Institute 
of Mental Health, National Institutes of Health 228 

Towns, Hon. Edolphus, a Representative in Congress from the State 
of New York, and chairman, Human Resources and Intergovernmental 
Relations Subcommittee: Opening statement 1 

Whittekin, Martie, president, National Nutritional Foods Association 160 

Letters, statements, etc., submitted for the record by: 

Bailey, Lynn B., Ph.D., nutrition professor, Food Science and Human 
Nutrition Department, University of Florida: Prepared statement 218 

Block, Gladys, Ph.D., University of California, Berkeley: Prepared state- 
ment 188 

Cordaro, J.B., president, Council for Responsible Nutrition: Prepared 

statement 131 

Hildwine, Regina, director, Technical Regulatory Affairs, National Food 
Processors Association: Prepared statement 174 

Huxtable, Ryan J., Ph.D., University of Arizona: Prepared statement 240 

Johnston, Richard, M.D., senior vice president, programs, and medical 
director, March of Dimes Birth Defects Foundation: Prepared state- 
ment 88 

McCaleb, Robert S., Herb Research Foundation: Prepared statement 367 

McNamara, Stephen H., Hyman, Phelps & McNamara, P.C., on behalf 
of the Utah Natural Products Alliance: Prepared statement 44 

Rosenberg, Irwin H., professor of medicine and nutrition, Tufts Univer- 
sity: Prepared statement 212 

Shank, Fred R., Ph.D., Director, Center for Food Safety and Applied 
Nutrition [CFSAN], Food and Drug Administration: 

Information concerning H.R. 1709 27 

Prepared statement 7 

Silverglade, Bruce, director, legal affairs, Center for Science in the Public 

Interest: Prepared statement 66 

(III) 



IV 

Page 

Letters, statements, etc., submitted for the record by — Continued 

Stark, Shirley, assistant attorney general of New York: Prepared state- 
ment 106 

Sternberg, Esther M., M.D., Chief, Unit on Neuroendocrine Immunology 
and Behavior, Clinical Neuroendocrinology Branch, National Institute 
of Mental Health, National Institutes of Health: Prepared statement .... 230 
Whittekin, Martie, president, National Nutritional Foods Association: 

Prepared statement 162 

APPENDIXES 

Appendix 1. — Answers from the scientists to questions from the Members 395 

Appendix 2. — Additional statements and materials for the record 457 



FEDERAL DRUG ADMINISTRATION'S 
REGULATION OF DIETARY SUPPLEMENTS 



TUESDAY, JULY 20, 1993 

House of Representatives, 

Human Resources and 
Intergovernmental Relations Subcommittee 
of the Committee on Government Operations, 

Washington, DC. 

The subcommittee met, pursuant to notice, at 10 a.m., in room 
2247, Rayburn House Office Building, Hon. Edolphus Towns (chair- 
man of the subcommittee) presiding. 

Present: Representatives Edolphus Towns, Thomas M. Barrett, 
Donald M. Payne, Steven Schiff, Stephen Horn, and Bernard Sand- 
ers. 

Also present: Ronald A. Stroman, staff director; William M. 
Layden and Brenda E. Pillors, professional staff members; Martine 
M. DiCroce, clerk; and Martha B. Morgan, minority professional 
staff, Committee on Government Operations. 

OPENING STATEMENT OF CHAIRMAN TOWNS 

Mr. Towns. The subcommittee will come to order. 

Today's hearing is on the Food and Drug Administration's regu- 
lation of dietary supplements. As required by the Dietary Supple- 
ment Act of 1992, on June 15 of this year, FDA proposed regula- 
tions governing nutrition labeling and nutrient content, and health 
claims for all dietary supplements. FDA also asked for comments 
on how it should regulate dietary supplements. Whether FDA is 
striking the proper regulatory balance is the focus of this hearing 
today. 

Millions of Americans regularly consume vitamins, minerals, 
herbs, and other dietary supplements to improve their nutrition 
and health. In recent years, growing scientific research has re- 
vealed that certain nutrients, such as vitamin E, may help to pre- 
vent heart disease and cancer. At a time when this country is try- 
ing to reduce health care costs and improve the health of all Ameri- 
cans, dietary supplements could contribute greatly to the preven- 
tion of disease. 

At the same time, consumers have a right to expect that their 
dietary supplements are safe and manufactured to the highest 
standards possible. Consumers also have a right to expect that 
claims made about the health and nutritional Deneflts of dietary 
supplements are truthful and nonmisleading. Consumers are sub- 
ject to a barrage of conflicting messages in the media about the po- 

(1) 



tential health benefits and health risks of certain nutrient supple- 
ments. 

We must all work together to avoid the tragedy that occurred in 
1989 when a contaminated batch of L-tryptophan was linked to a 
deadly disease known as EMS. In 1991, this subcommittee, under 
the leadership of my predecessor, the late Honorable Ted Weiss, 
Democrat of New York, heard firsthand from some of the innocent 
persons who were harmed by L-tryptophan. Today we will have an 
opportunity to follow up on that initial inquiry. 

It is time to cut through the regulatory fog surrounding dietary 
supplements and hear from the experts about: (1) FDA's actual and 
proposed regulations for dietary supplements; (2) the public health 
risk and benefits of dietary supplements; (3) the scientific data sup- 
porting health claims for dietary supplements; and (4) the proper 
regulatory balance between consumer protection and free trade. 

I look forward to hearing from our witnesses this morning. Be- 
fore we hear from our first witness, I would like to yield to Mr. 
Schiff, the ranking minority member of the subcommittee, for any 
remarks that he might have at this time. 

Congressman Schiff. 

Mr. Schiff. Thank you very much, Mr. Chairman. I will cer- 
tainly be brief. We have a lot of qualified witnesses to hear from. 

I want to, first of all, thank you for holding this hearing. The 
subject of dietary supplements, I think, doesn't receive as much 
media attention as certain other issues we are seeing today. Never- 
theless, I can tell you that from the volume of mail I receive from 
my constituents, there is obviously great public interest in this sub- 
ject; and I want to thank you personally for holding this hearing. 

I am an original cosponsor of Congressman Bill Richardson's bin, 
H.R. 1709, which we believe will strike a balance — the balance that 
you referred to — between the responsibility of the FDA to look after 
those substances which we consume and the right of people to se- 
lect dietary supplements if they choose to do so without inter- 
ference from the government that goes beyond the government's le- 
gitimate interest in protecting public health and safety. 

I would be interested, from any or all of the witnesses in the 
course of their testimony, if they nappen to be familiar with H.R. 
1709, if they would express their support or nonsupport, if that is 
the case, of that bill. We, the sponsors, believe that we are achiev- 
ing the correct balance, but I would be interested in other views 
on that. 

And with that, I want to, again, say that I think this is a very 
important hearing; and I look forward to it. And I yield back. 

Mr. Towns. Thank you very much. 

Congressman Sanders. 

Mr. Sanders. Thank you Mr. Chairman. I will also be brief. This 
is an extremely important hearing and, as Congressman Schiff has 
mentioned, has generated a lot of interest in my State of Vermont. 
I have been a strong supporter for a person's right to seek alter- 
native approaches in medical care. It is clear that western medicine 
does not have all the answers. I am supportive of a new program 
which provides grants for alternative health research. 

In September, we will be holding a conference in Vermont actu- 
ally on cancer prevention looking at diet and the environmental 



causes of cancer. And so this is an issue of great concern in my own 
State. There is little doubt that in many cases the FDA and the 
medical establishment have been intolerant of those who practice 
alternative medicine while they have been more than willing to 
give the benefit of the doubt to corporate sponsors. 

For corporations, the FDA has been content to approve products 
solely on test claims provided by the very industries which the 
FDA is supposed to regulate. In fact, for me, this was one of the 
most upsetting revelations of the silicone breast implant and BGH, 
bovine growth hormone, investigations. But I think what we all 
want to see is a balance. 

Many of us believe that every American has the right to look at 
alternative health approaches. At the same time, we don't want to 
see unscrupulous manufacturers producing and selling misleading 
products to, often, the most vulnerable members of society, those 
that are very ill or uneducated. 

And so how you look at a balance for Americans who want to 
look at alternative approaches to health care have that opportunity 
and so that other people are not exploited, I think, is the issue here 
today. 

Mr. Towns. Thank you. 

Before we begin, I would like to say to all our witnesses who will 
be presenting testimony today that the full text of the statement 
that you submit will be included in the record. I would like to ask 
each of you to summarize your testimony in approximately 5 min- 
utes so that we will have time to ask questions. 

Let me welcome our first panel, Dr. Fred Shank. 

Please come forward. 

Mr. Schiff. While the witness is coming up, Mr. Chairman, I 
want to emphasize, for the other witnesses, what you just said. My 
experience — the chairman announces that full written statements 
are part of the record and people read the written statements. I 
want to guarantee that full written statements are made a part of 
the record and encourage summaries. 

Thank you. 

Mr. Towns. Thank you very much. 

Let me welcome our first panel, Dr. Fred Shank of the Food and 
Drug Administration. 

And, Dr. Shank, if you would, please introduce the people that 
are with you in terms of their role with the FDA. We would appre- 
ciate it. 

Dr. Shank. Thank you, Mr. Chairman. 

On my right is Mr. Mitch Zeller from the Office of the Deputy 
Commissioner for Policy. On my left is Mr. Robert Lake who is the 
Director of Office of Policy, Planning and Strategic Initiatives with- 
in the Center for Food Safety and Applied Nutrition. And Dr. Lori 
Love is the Director of the Center's Clinical Research and Review 
Staff. 

Mr. Towns. Thank you very much. 

It is our custom to ask all witnesses who present testimony to 
the subcommittee to be sworn in. So if you would please stand. 

[Witnesses sworn.] 

Mr. Towns. You may be seated. 



4 

Let the record show that the witnesses answered in the affirma- 
tive. And thank you very much. 
You may proceed any way you so desire. 

STATEMENT OF FRED R. SHANK, PhX)., DIRECTOR, CENTER 
FOR FOOD SAFETY AND APPLIED NUTRITION [CFSAN], FOOD 
AND DRUG ADMINISTRATION, ACCOMPANIED BY MITCHELL 
ZELLER, OFFICE OF THE DEPUTY COMMISSIONER FOR POL- 
ICY; ROBERT LAKE, DIRECTOR, OFFICE OF POLICY, PLAN- 
NING AND STRATEGIC INITIATD7ES; AND LORI LOVE, Ph.D., 
DIRECTOR, CLINICAL RESEARCH AND REVffiW STAFF 

Dr. Shank. Mr. Chairman and members of the subcommittee, we 
are here today to talk to you about FDA's current rulemaking ac- 
tivities concerning dietary supplements and to review with you 
some of the results of investigations regarding the association be- 
tween some dietary supplements, including L-tryptophan, and pub- 
lic health concerns. FDA published three proposed rules in June 
18, 1993, which will be a part of our considerations this morning. 

Part of the challenge in discussing dietary supplements is under- 
standing how broadly the term "dietary supplement" is being used. 
The term "dietary supplement" refers to everything from tradi- 
tional vitamin and mineral supplements to amino acids, herbs, and 
many other products. 

The vast majority of dietary supplements consists of traditional 
vitamins and minerals and do not raise serious health concerns. 
We believe that these products represent about 80 percent of the 
market. The remaining products on the market, high potency 
amino acids, herbs, ana other substances do raise questions about 
safety and labeling. Many of these products have no recognized role 
in nutrition and frequently bear express or implied disease claims 
and have been marketed for specific therapeutic purposes. 

FDA has traditionally regulated dietary supplements under the 
authority of the Food, Drug, and Cosmetic Act on a case-by-case 
basis based on complaints or other information brought to the 
agency's attention concerning a product's safety or labeling. FDA's 
primary goal is to ensure that dietary supplements are safe and 
that the claims made for these products are truthful, not mislead- 
ing, and properly supported by the scientific evidence. 

Of its field force of over 3,000 employees, FDA devotes only ap- 
proximately 15 to 20 person years, that is full-time employee 
equivalents, each year to the compliance activities involving dietary 
supplements; and this is done principally through the agency's es- 
tablished health fraud program which was issued in June 1987. 

Now, I would like to briefly bring you up to date on the results 
of the investigations regarding the association between L-trypto- 
phan and eosinophilia myalgia syndrome or EMS. Despite recent 
intense research, the exact cause of EMS and an understanding of 
how it develops has not been established, and research continues. 
Current findings support previous suggestions that the L-trypto- 
phan associated EMS was caused by several factors and is not only 
related to impurities in a single source of L-tryptophan. 

On the Federal Register documents, first trie advanced notice of 
proposed rulemaking announced that the FDA is reviewing the 
manner in which it regulates the safety of dietary supplements. As 



discussed in this announcement, FDA is reviewing the current reg- 
ulatory policies because significant changes in the dietary supple- 
ment market and the consumer's use of supplements have occurred 
in recent years. Not only is the market growing, but FDA is becom- 
ing increasingly aware of reports of serious health problems associ- 
ated with the ingestion of dietary supplements. 

The ANPR noted that while many ingredients in herbal dietary 
supplements have not been associated with specific health con- 
cerns, some components contained in these products have been as- 
sociated with adverse health effects or toxicities in animals or hu- 
mans. For example, at least six documented cases of toxic hepatitis 
have been associated with the consumption of chaparral. And I 
could go on with other examples of other compounds, but this is 
contained in our written testimony. 

In May 1991, following the EMS outbreak associated with the 
consumption of L-tryptophan-containing dietary supplements, the 
Commissioner of Foods and Drugs, Dr. Kessler, established an in- 
ternal FDA task force to review the agency's regulatory program on 
dietary supplements. FDA has made the recommendations of this 
task force available to the public. It must be emphasized that none 
of the recommendations in this task force report represents agency 
policy. The agency will review the comments received and then de- 
cide what actions appear to be appropriate in the future. 

The other Federal Register documents that are of interest this 
morning pertain to the proposed rule on health claims for dietary 
supplements. The agency proposed to make claims for these prod- 
ucts subject to the general requirements that apply to claims for 
other types of food. This proposed rule was mandated by the Nutri- 
tion Labeling and Education Act. Its timing was determined by the 
Dietary Supplement Act. 

While the Nutrition Labeling and Education Act mandated a 
health claims standard for conventional foods, the statute ordered 
FDA to establish a health claims standard for dietary supplements. 
In November 1991, FDA proposed that health claims for dietary 
supplements should be based on the same standard as conventional 
foods, namely, significant scientific agreement. The agency's ration- 
ale for identical standards was simple: The vitamin C in capsules 
should be subject to the same standard as vitamin C in orange 
juice. In June, FDA again proposed that the health claims standard 
for dietary supplements should be one of significant scientific 
agreement. 

FDA is dedicated to assisting Americans in capitalizing on the 
scientific advances over the past 30 years that have expanded our 
understanding of the relationship between health and diet and of 
the role that diet can play in improving the health of Americans. 
FDA encourages positive changes in dietary habits and recognizes 
that consumer's access to adequate nutrition and health informa- 
tion is an important part of this process. 

Finally, Mr. Chairman, if time permits, I am going to briefly talk 
about our future role concerning health claims for folic acid and the 
antioxidant vitamins. Even though the agency's advisory committee 
has not yet fully resolved certain issues involving folic acid, in an 
effort to progress, the agency will publish a proposal to authorize 



health claims on the labels and labeling of foods and dietary sup- 
plements relating to folic acid and the risk of neural tube defects. 

Later this month, FDA intends to publish a proposal providing 
an opportunity for the submission of comments and new data to 
FDA on the relationship of antioxidant vitamins and cancer. FDA 
plans to cosponsor, with other research and health organizations, 
an open symposium to discuss the available science, identify any 
other research needs and discuss ways of facilitating research. FDA 
will consider the results of this symposium in deciding whether to 
authorize a health claim for antioxidant vitamins and cancer. 

Mr. Chairman, that concludes our testimony; and we would be 
happy to respond to your questions. 

[The prepared statement of Dr. Shank follows:] 




DEPARTMENT OF HEALTH & HUMAN SERVICES 



Public Health Service 



Food and Drug Administration 
Rockville MD 20857 



STATEMENT BY 

FRED R. SHANK 

DIRECTOR 

CENTER FOR FOOD SAFETY AND APPLIED NUTRITION 

FOOD AND DRUG ADMINISTRATION 

PUBLIC HEALTH SERVICE 

DEPARTMENT OF HEALTH AND HUMAN SERVICES 



BEFORE THE 

SUBCOMMITTEE ON HUMAN RESOURCES AND 

INTERGOVERNMENTAL RELATIONS 
COMMITTEE ON GOVERNMENT OPERATIONS 



JULY 20, 1993 



12 fiE RELEASED ONLY UPON DELIVERY 



8 



Mr. Chairman and Members of the Subcommittee: 

I am Fred Shank, Director of the Food and Drug Administration's 
(FDA) Center for Food Safety and Applied Nutrition (CFSAN) . I am 
accompanied today by Robert Lake, Director of the Office of 
Policy, Planning and Strategic Initiatives within CFSAN, Mitchell 
Zeller from the Office of the Deputy Commissioner for Policy, and 
Dr. Lori Love, Director of CFSAN 's Clinical Research and Review 
Staff. 

We're here today to talk to you about FDA's current rulemaking 
activities concerning dietary supplements and to review with you 
some of the results of investigations regarding the association 
between some dietary supplements, including L-tryptophan, and 
public health concerns. 

As you know, FDA published three proposed rules on June 18, 1993, 
to fulfill requirements imposed on FDA by the Nutrition Labeling 
and Education Act of 1990 (NLEA) and the Dietary Supplement Act 
(DSA) of 1992. FDA also published on June 18 an advance notice 
of proposed rulemaking (ANPR) to announce that we are reviewing 
the manner in which we regulate the safety of dietary supplements 
and that FDA intends to bring amino acid-containing dietary 



2 
supplement products (including L-tryptophan) into compliance with 
the law. 

Before I discuss the Agency's views about the safety and labeling 
of dietary supplements and the thinking behind our rulemaking 
activities, I'd like to briefly discuss the history and legal 
framework under the Federal Food, Drug, and Cosmetic (FDC) Act of 
how FDA has regulated dietary supplements. 

HOW FDA REGULATES DIETARY SUPPLEMENTS 

Part of the challenge in discussing dietary supplements is 
understanding how broadly the term "dietary supplement" is being 
used. The term "dietary supplement" refers to everything from 
the traditional vitamin and mineral nutritional supplements to 
amino acids, herbs, and many other products. 

The vast majority of dietary supplements consist of traditional 
vitamins and minerals and do not raise serious health concerns. 
We believe that these products represent about 80 percent of the 
market. The remaining products on the market — amino acids, 
herbs, and other substances--do raise questions about safety and 
labeling. Many of these products have no recognized role in 
nutrition, frequently bear express or implied disease claims, and 
have been marketed for specific therapeutic purposes. 



10 



3 
FDA has traditionally regulated dietary supplements under the 
authority of the FDC Act on a case-by-case basis, based on 
complaints or other information brought to the Agency's attention 
concerning a product's safety or labeling. FDA's primary goal is 
to ensure that dietary supplements are safe and that the claims 
made for these products are truthful, not misleading, and 
properly supported by scientific evidence- 
Under the FDC Act, FDA's regulation of dietary supplements is 
grounded in both the food and drug provisions. Some substances 
used in dietary supplements fall within the food definition 
(section 201(f)) because they are used for nutritional value. 
Some dietary supplements, such as those marketed with therapeutic 
claims, fall within the drug definition (section 201(g)) because 
they are intended to prevent or treat disease or to affect the 
structure or function of the body. Some products fall within 
both the food and drug definitions and are regulated accordingly. 
The FDC Act has never contained a statutory framework for dietary 
supplements outside of the food and drug provisions. 

Because dietary supplements are subject to regulation as foods, 
drugs, or both, there are a variety of statutory provisions that 
come into play in the regulation of these products. These 
provisions, which may form the basis of a charge that a product 
has been marketed unlawfully in interstate commerce, include: 



11 



4 
section 402(a)(1) — foods containing a poisonous or 
deleterious added substance that may render the product 
injurious, 

section 402(a)(2)(C) — foods that are unsafe within the 
meaning of section 409 because the product is, bears, 
or contains a food additive that is not listed by FDA, 

section 403(a) — foods with false or misleading 
labeling, 

section 409(a) — unsafe food additives, 

section 501(a)(2)(B) — drugs not prepared under current 
good manufacturing practice, 

section 502(a) — drugs with false or misleading 
labeling, 

section 502(f)(1) — products failing to bear adequate 
directions for use, 

section 503 — prescription drugs dispensed without a 
prescription, and 



12 



5 
section 505(a) — new drugs that are marketed without FDA 
approval. 

As noted above, section 409 forms the basis for one of these 
charges, where the product is, bears, or contains a food additive 
that is not listed (approved) by FDA. Section 409 was added to 
the FDC Act by the Food Additives Amendment of 1958, a 
significant change in the regulatory framework for these 
products. The 1958 amendment resulted from a determination by 
Congress that allowing vendors of processed foods to introduce 
ingredients into their products without first establishing the 
safety of those ingredients would leave consumers vulnerable to 
unsafe products until FDA was able to establish that the 
ingredients are injurious and then secure their removal from the 
marketplace. In 1958, Congress expressly decided to shift the 
burden of proving safety to the proponents of the ingredients. 
This action was deemed essential to protect the public health 
because there are simply too many substances used in food for FDA 
to bear the burden of determining the safety of such ingredients, 
with the resources available to the Agency and given other 
competing priorities. 

Vitamins, minerals, amino acids, herbs, and other ingredients 
that are processed into finished food products, such as dietary 
supplements in pill, capsule, powder, or liquid form, are subject 
to regulation by FDA under the food additives provision of the 



13 



6 
FDC Act, unless they are generally recognized as safe (GRAS) or 
prior-sanctioned. (A substance is considered "prior-sanctioned" 
if its specific use in food was approved by FDA or the Department 
of Agriculture prior to September 6, 1958.) A "food additive" is 
broadly defined in section 201 (s) as any substance the intended 
use of which results or may reasonably be expected to result, 
directly or indirectly, in its becoming a component or otherwise 
affecting the characteristics of any food. Substances that are 
GRAS for their intended use, and ingredients that are subject to 
prior sanctions, however, are excepted from the food additive 
definition and are not subject to premarket approval. Some food 
ingredients are marketed based on independent determinations of 
their GRAS status. Any ingredient in food may lose its GRAS 
status and become a food additive if a safety question arises. 

Products containing food additives that are not listed by the 
Agency are deemed unsafe within the meaning of section 409, 
causing them to be adulterated under section 402(a)(2)(C) of the 
FDC Act. Adulterated products in interstate commerce, as well as 
their vendors, are subject to regulatory action. 

Food substances that are not food additives remain subject to the 
other food provisions of the FDC Act, section 402 on adulteration 
and section 403 on misbranding. 



14 



7 
Having just outlined FDA's regulatory responsibilities concerning 
foods including dietary supplements under the FDC Act, I'd like 
to describe briefly our enforcement policy with regard to those 
responsibilities . 

The Agency has, in its enforcement policy, generally addressed 
dietary supplements in the same manner that it has addressed 
conventional foods, focusing on products that raise significant 
safety or consumer deception issues. 

Section 409 is employed in a small number of these cases, where 
there are products that contain unapproved food additives that 
raise safety concerns. The application of section 409 is 
consistent with Congress' intent in passing the 1958 Food 
Additives Amendment and is vital to the protection of the public 
health in cases like L-tryptophan and other cases in which there 
is concern over the safety of a food ingredient. 

Of its field force of over 3,000 employees, FDA devotes 
approximately 15 to 20 person years (full time employee 
eguivalents) per year to compliance activities involving dietary 
supplements, principally through the Agency's established "health 
fraud" program which operates under a Compliance Policy Guide 
(CPG) that was issued in June 1987. 



15 



8 
The CPG describes FDA's two priorities for enforcement activities 
involving dietary supplements, in order of importance, as 
follows: 

(1) products that are potentially harmful when used as 
directed or in a customary manner (a direct health 
hazard posing a risk of serious or life-threatening 
adverse health effect) ; 

(2) products bearing misleading or deceptive claims 
posing a significant risk of adverse health effects (an 
indirect health hazard resulting from the delay or 
discontinuance of appropriate medical treatment) . 

Mr. Chairman, the rest of my testimony will focus on (1) 
bringing you up to date on the results of investigations 
regarding the association between the use of L-tryptophan and 
eosinophilia myalgia syndrome, (2) discussing the two June 18, 
1993 Federal Register publications in which you have expressed an 
interest, and (3) giving you a status report on FDA's 
consideration of health claims for dietary supplements containing 
folic acid and antioxidant vitamins. 

L-tryptophan 



16 



9 
As you know, because FDA has no direct authority to remove 
products from the market, FDA requested a voluntary recall on 
November 17, 1989, of the amino acid L-tryptophan after published 
reports associated its ingestion with an epidemic of a connective 
tissue disease called eosinophilia myalgia syndrome (EMS) . More 
than 1,500 injuries and 38 deaths, were reported to public health 
agencies, although the incidence of this disorder is thought to 
be much higher. 

Despite recent intense research, the exact cause of EMS ana an 
understanding of how it develops have not been established. 
Initial epidemiological studies implicated the L-tryptophan 
produced by a single Japanese manufacturer and suggested a role 
for some impurity or other compound in these batches of L- 
tryptophan in the etiology of EMS. However, both initial and 
subsequent epidemiological studies on the EMS epidemic have 
identified cases of EMS, and another related disease, 
eosinophilic fasciitis, that occurred before the 1989 epidemic 
and that appear to be related to other batches or sources of L- 
tryptophan. Other data indicate that L-tryptophan, either alone 
or in combination with some other component in the supplement 
products, may be responsible for some of the pathoxogical 
features in EMS. Taken together, these findings support previous 
suggestions that the L-tryptophan-associated EMS was caused by 
several factors and is not solely related to an impurity in a 
single source of 



17 



10 
L-tryptophan . 

Mr. Chairman, let me proceed to the two June 18, 1993 Federal 
Register documents that are of interest to you. 

First, the advance notice of proposed rulemaking (ANPR) announced 
that FDA is reviewing the manner in which it regulates the safety 
of dietary supplements, including products containing vitamins, 
minerals, amino acids, herbs, and other similar nutritional 
substances. FDA requested public comment on the approaches, 
consistent with the requirements of the FDC Act, for assuring the 
safety of such products offered as dietary supplements. Also, 
FDA announced its intention to bring amino acid-containing 
dietary supplement products into compliance with the law and 
requested that manufacturers of these products submit any 
additional information that may be available on the safety and 
use of individual amino acids or combinations of amino acids as 
ingredients in dietary supplements. 

As discussed in the ANPR, FDA is reviewing the current regulatory 
policies because significant changes in the dietary supplement 
market and in consumers' use of supplements have occurred in 
recent years. Not only is the market growing, but FDA is 
becoming increasingly aware of reports of serious health problems 
associated with the ingestion of dietary supplements. In 
addition to these factors, FDA was directed to review its 



18 



ii 

regulatory policies with respect to dietary supplements by the 
enactment of the Dietary Supplement Act (DSA) , led the Agency to 
institute its review and publish this ANPR. 

The ANPR noted that while many ingredients in herbal dietary 
supplements have not been associated with specific health 
concerns, some components contained in these products have been 
associated with adverse health effects or toxicities in animals 
and humans. For example, at least six documented cases of toxic 
hepatitis have been associated with the consumption of chaparral 
(larrea tridentata ) . There have been several cases of adverse 
reactions associated with the consumption of dietary supplements 
containing Lobelia inf lata (lobelia, Indian tobacco) . Germander 
(genus Teucrium ) has been recently implicated in at least seven 
cases of acute nonviral hepatitis in France. Chronic renal 
failure has been reported to have resulted from consumption of 
dietary supplements containing Stephania tetrandra and Magnolia 
officinalis . 

The use of yohimbe in dietary supplements such as body building 
products appears to be increasing. The known pharmacologically 
active components of yohimbe are yohimbine and related alkaloids. 
Yohimbine is an approved drug and is used as a vasodilator. Other 
effects of yohimbine include lowering of blood pressure and 
antagonism of neurotransmitters and their precursors. 



19 



12 
Human toxicity, including fatalities have been associated with 
consumption of the Symphytum (comfrey and Russian comfrey) , 
Heliotropium . and Senecio species. The scientific literature 
documents the toxicity of these and other pyrrolizidine alkaloid 
(PA) -containing plants. There are reports that PA causes liver 
injury and failure secondary to veno-occlusive disease (i.e., 
blocking the veins that remove blood from the liver) . Toxicity 
associated with PA-containing plants can occur, and has occurred, 
after relatively short use (a few weeks) and at relatively low 
doses. Several animal studies have demonstrated that PAs and PA- 
containing plant materials (comfrey) can cause cancer in test 
animals. 

In May 1991, following the EMS outbreak associated with 
consumption of L-tryptophan-containing dietary supplements, the 
Commissioner of Food and Drugs established an internal FDA task 
force to review the Agency's regulatory program for dietary 
supplements and to recommend improvements. Known as the Dietary 
Supplement Task Force (the Task Force) , it was composed of Agency 
staff with experience and expertise in regulatory, nutritional, 
legal, and medical issues related to supplements. The 
Commissioner asked the Task Force to examine a number of issues, 
including whether safety concerns exist regarding dietary 
supplements and, if so, to recommend a regulatory framework to 
distinguish supplements that raise safety concerns from those 
that do not. 



20 



13 
The Task Force completed its work in May 1992 when it submitted a 
report with recommendations to the Commissioner. 

It must be emphasized that nothing in the Task Force report 
represents Agency policy. FDA has made the recommendation of the 
Task Force available for public comment. The Agency will review 
the comments it receives and then decide what actions appear to 
be appropriate. 

The other Federal Register document of particular interest to you 
is the proposed rule on health claims for dietary supplements of 
vitamins, minerals, herbs, or other similar substances. The 
Agency proposed to make claims for these products subject to the 
general reguirements that apply to claims for other types of 
food. This proposed rule was mandated by NLEA. Its timing was 
determined by the DSA. 

Under NLEA, Congress for the first time authorized FDA to 
regulate health claims on food and dietary supplement labels and 
in food labeling. The new provisions amended the FDC Act by 
providing that a product is misbranded if it bears a claim that 
characterizes the relationship of a nutrient to a disease or 
health-related condition, unless the claim is made in accordance 
with the regulation that authorizes the use of the claim. 



21 



14 
Congress enacted the health claims provisions of the 1990 
amendments to give U.S. consumers nutritional information that 
may be important in maintaining their health and to protect these 
consumers from unfounded health claims. The House Report of 
June 13, 1990 states, "Health claims supported by a significant 
scientific agreement can reinforce the Surgeon General's 
recommendations and help Americans to maintain a balanced and 
healthful diet." In addition, the Statement of the House Floor 
Managers noted that "There is a great potential for defrauding 
consumers if food is sold that contains inaccurate or 
insupportable health claims." The House Report characterized the 
need for regulation of health claims as "compelling." 

While NLEA mandated a health claims standard for conventional 
foods, the statute ordered FDA to establish a health claims 
standard for dietary supplements. In November 1991, FDA 
proposed that health claims for dietary supplements should be 
based on the same standard as conventional foods, namely, 
significant scientific agreement. The Agency's rationale for 
identical standards was simple: vitamin C capsules should be 
subject to the same standard as Vitamin C in broccoli or orange 
juice. In the June 18 Federal Register . FDA again proposed that 
the health claims standard for dietary supplements should be one 
of significant scientific agreement. 



22 



15 
While FDA did not propose any specific health claims for dietary 
supplements in the June 18 Federal Register . FDA does, however, 
contemplate further proceedings where the nutrient/disease 
relationships have not been resolved with respect to dietary 
supplements (i.e., for dietary fiber and cardiovascular disease, 
dietary fiber and cancer, zinc and immune function in the 
elderly, and omega-3 fatty acids and coronary heart disease, and 
antioxidant vitamins and cancer) . 

FDA is dedicated to assisting Americans in capitalizing on the 
scientific advances over the last 3 years that have expanded the 
understanding of the relationship between health and diet and of 
the role that diet can play in improving the health of Americans. 
FDA encourages positive changes in dietary habits and recognizes 
that consumers' access to adequate nutrition and health 
information is an important part of this process. 

Finally, Mr. Chairman, I am going to discuss where the Agency is 
in regard to health claims for folic acid and antioxidant dietary 
supplements. 

Folic Acid 

Even though the Agency's Food Advisory Committee has not yet 
fully resolved certain issues involving folic acid, in an effort 
to progress as expeditiously as possible, the Agency will publish 



23 



16 
in the near future a proposal to authorize health claims on the 
labels and labeling of foods and dietary supplements relating to 
folic acid and the risk of neural tube defects. 

Antioxidant vitamins 

Later this month, FDA intends to publish a proposal that will 
provide an opportunity for the submission of comments and new 
data to FDA on the relationship of antioxidant vitamins and 
cancer. FDA plans to co-sponsor, with other research and health 
organizations, an open symposium to discuss the available 
science, to identify any unmet research needs, and to discuss 
ways of facilitating research to meet these needs. FDA will 
consider the results of this symposium in deciding whether to 
authorize a health claim on antioxidant vitamins and cancer. 

Mr. Chairman, that concludes our testimony. We would be happy to 
respond to any questions. 



24 

Mr. Towns. Thank you very much, Dr. Shank. 

Aside from the L-tryptophan EMS incident, exactly how preva- 
lent are any safety problems associated with dietary supplements? 

Can you quantify the number of Americans that are adversely af- 
fected each year? 

Dr. Shank. Mr. Chairman, we do not have that type of avail- 
able — that data available before us. I would point out that I called 
your attention to the fact that we are not concerned with at least 
80 percent of that market out there. We do not believe that that 
presents a safety concern. 

Second, I spoke during the testimony about our concern relative 
to chaparral. There have been several cases of adverse reactions as- 
sociated with consumption of dietary supplements containing Lobe- 
lia. Germander has recently been indicated in seven cases of acute 
nonviral hepatitis in France. Chronic renal failure has been re- 
ported to result from the consumption of dietary supplements con- 
taining Chinese herbal products. 

Mr. Towns. Back to the point you made in reference to the exact 
cause of the L-tryptophan-associated EMS incident, why is it so 
hard to pin down the problem? 

Dr. Shank. Mr. Chairman, this is a problem that is underpinning 
all of these actions that we are dealing with today. The science is 
advancing, without question. We know more about the positive ben- 
efits of diet and food. We are also learning some of the negative as- 
pects as we expand our science. 

In other words, certain food components and nutrients do have 
some detrimental impacts. The research we are doing relative to L- 
tryptophan has taught us a great deal. We started out believing 
that we were primarily concerned about a contaminant. We no 
longer believe that to be the case. 

There is, we believe, probably an interaction between a possible 
contaminant and L-tryptophan. On the other hand, we just do not 
have the data to answer your question as to what, specifically, is 
the problem here. 

Mr. Towns. So you are saying that, generally, dietary supple- 
ments are safe? 

Dr. Shank. I am saying that 80 percent of the market we believe 
to present no safety concerns. We do believe that there are signifi- 
cant safety concerns relative to certain amino acids such as L-tryp- 
tophan, as well as herbal preparations. 

Mr. Towns. Thank you very much, Dr. Shank. 

I yield to the ranking minority member, Mr. SchifT. 

Mr. SCHIFF. Thank you, Mr. Chairman. 

Dr. Shank, from many conversations I have had with my con- 
stituents who use dietary supplements and the letters I have re- 
ceived from others, I think I can put together at least a generality 
of the view — and I stress this is a generality, it may not fit any in- 
dividual. But the generality — the consensus of view would be this: 
There is general agreement among those who use dietary supple- 
ments that the FDA has a legitimate role in this area certainly. 
Particularly if a specific health claim is made for a product, as is 
the case for a food product that is not a dietary supplement. 

The FDA has a role in requesting the proof that goes behind 
that, if you will, advertising claim. 



25 

Further, if there is a specific, known, provable, health hazard in 
the use of a specific substance, once again, just like with any other 
substance, it is the role of the FDA to pursue that further. But 
there is a general expressed concern that the FDA intends to go 
further and would like to go further in terms of eliminating or reg- 
ulating dietary supplements. And there is enormous opposition to 
this perceived view on the part of the FDA. 

And the perceived view is that the FDA would like to either 
eliminate whole categories of dietary supplements or to require 
that they be dispensed only through a medically advised prescrip- 
tion. You are nodding, and you obviously know what I am talking 
about. Have I given you enough information to respond to that par- 
ticular concern? That is the concern I am hearing. 

Dr. Shank. I would like to make a couple of points. FDA does 
not intend — does not desire to take dietary supplements off the 
market nor do we consider it appropriate to treat all dietary sup- 
plements as drugs as some have suggested. That is not what the 
intention of the agency is. 

I think the challenge that all of us face — the consumers, the in- 
dustry, the Congress, and the FDA — is to strike that proper bal- 
ance to ensure the safety of these products and make sure that 
they are properly labeled while providing the consumers freedom of 
choice. 

Mr. Schiff. All right. Do you happen to be familiar at this time 
with H.R. 1709, which I referred to? It is drafted by my colleague, 
Congressman Richardson of New Mexico. I and a number of others 
are original cosponsors and subsequent cosponsors. We are at- 
tempting to arrive at that balance in this legislation. Are you famil- 
iar enough with it to express an opinion on that bill? 

Dr. Shank. I would like to refer that question to my colleague 
from the Office of Policy. 

Mr. Zeller. Mr. Schiff, FDA has yet to take an official public po- 
sition on the legislation. But we can discuss some of the general 
issues that the legislation poses, and I would be happy to do that. 

The Richardson legislation would make a fairly fundamental 
change in the manner in which FDA regulates both the safety and 
the labeling of dietary supplements. Under current law on the safe- 
ty side, there are a number of tools available that the agency would 
no longer have access to under this legislation. Tools that, if we 
have to go to court, would make it easier for us to prevail. Under 
the current law, there are certain burdens to demonstrate safety 
that exist on the manufacturer. If the Richardson legislation 
passes, the burden would be shifted to FDA to demonstrate that 
something is harmful. 

On the labeling side, you talked in your preliminary remarks 
about having FDA perform some kind of role looking at the data 
for claims before the claims could be made, if I understood what 
you were saying. The Richardson legislation provides no such role 
for FDA to be able to examine the data supporting the claims be- 
fore the claim could be made. 

The Richardson bill does say that a company has to notify the 
agency 30 days prior to making a claim, but there is no premarket 
review of the science. Now, under the Nutrition Labeling and Edu- 
cation Act for foods, Congress very clearly said that, before a food 



26 

company could make a health claim on the label, the data would 
have to be presented to FDA. And under the standard of significant 
scientific agreement, FDA would give it either a thumbs up or 
thumbs down. The Richardson legislation has a very different ap- 
proach. 

So those are the kinds of general issues that the Richardson bill 
poses, and those are the choices that Congress has to make. 

What it comes down to is what regulatory role, if any, does Con- 
gress think the FDA should be performing in reviewing safety and 
labeling? We all can agree in principle that consumers should have 
access to products that are safe and that bear claims that are sci- 
entifically valid. No one disagrees with that as a general statement 
of where we ought to be. The disagreement is over how we ought 
to get there. 

Mr. Schiff. Two other things. 

Can I take one more minute? 

Mr. Towns. Sure. 

Mr. Schiff. Thank you, Mr. Chairman. 

I would invite, at your convenience, a paragraph -by-paragraph 
analysis of H.R. 1709. 

I don't think either Congressman Richardson, nor I, nor any 
other sponsor are wedded to any specific wording; and if there are 
wordings that the FDA would like us to review, we welcome them. 

[The information referred to follows:] 



27 



H.R. 1709 

RICHARDSON - (Originally oosponsored by Inhofe, Schifl, Norton, Boehlert, Towns, 
Bcehuer, Frost, Pelosi, Peterson of MN, Hall of TX, Upton, and Pallonc) 



Section 1. Short Title 

"Dietary Supplement Health and Education Act of 1993" 

Section 2. Definitions 

Amends Section 201 of the FD&C Act to define "dietary supplement'' as a food for special 
dietary use that includes one or more vitamins, minerals, herbs, amino acids, or other 
ingredients for use by man to supplement the diet, including concentrates and extracts, 
and is intended for use in tablet, capsule, powder, softgel, or any other form (including 
liquid) that is not represented for use as conventional food or as a sole item of a meal or 
diet. 

Exempts dietary ingredients intended for use in dietary supplements from the definition 
of food additive. 

Section 3. Dietary Supplement Labeling and Composition (Adulteration and Misbrand- 
ing) 

Adulteration 

Amends Section 402 of the FD&C Act to deem a dietary supplement adulter- 
ated if: 

1) The Secretary determine* that an ingredient presents a substantial and unreasonable 
risk of illness or injury; 

2) It contains an ingredient that has not had safety adequately substantiated through 
evidence of safe history of use, well-designed scientific studies, or "other appropriate 
means;" or 

3) The Secretary was not notified about a yignifiMyt, change in manufacturing practice or 
potential safety or contamination problems during production; unless; 



e The Secretary or the National Academy of Sciences have established a recommended 
daily allowance or eatunaied safe and adequate dietary intake for the ingredient 

o Requires the Secretary to issues regs within 18 months of enactment to require manufac- 
turers to notify the Secretary of significant changes in manufacturing practices or poten- 
tial safety or contamination problems. 



30"d 28E2-S2S-3K-6 Qi tHO/WOd UGMd C0:BI fr66T-TI-a*l 



28 



Compositional Limits (Proxmire Amendment Provisions) L 

A meads Section 411 of the FD&C Act to prohibit the Secretary from doing the following 
(except with respect to individuals in the treatment or management of specific diseases, 
children, or pregnant or lactating women): 

1) Establishing maximum potency limits on dietary supplements; 

2) Classifying dietary supplements as drugs solely because they exceed potency level 
the secretary determines to be nutritionally rational or useful; or 

3) limiting combination or number of ingredients in dietary supplements. 

Misbranding 

Amends Section 403 of the FD&C Act (misbranding provisions) to require dietary supple- 
ment labels to include: 

1) Declaration of ingredients; 

2) Product identification statements; 

3) Declaration of the part of the plant from which ingredients are derived; 

4) Adherence to official compendia requirements for composition, strength, quality, and 
purity unless plainly stated on the label otherwise; and 

5) Accurate representation of composition, strength, purity, or quality the product pur- 
ports to have if not subject to official compedia requirements. 



o Permits dietary supplements that meet U.S. Pharmacopeia (USP) requirements to be 
labeled with USP designation. 

o Prohibits dietary supplements from being considered drugs because of USP designa- 
tion. 

Section 4. Claims 

Exempts dietary supplements from NLEA health claim requirements. 
Permits dietary supplements to make disease-related claims if: 

o The Secretary has authorized the claim and characterization of the claim is consistent with 
this authorization; 

o The Secretary has not determined (after rulemaking based on totality of scientific evi- 
dence) that the nutrient's consumption in a dietary supplement would be different from 
its consumption in a food; or 

o Characterization of claim accurately represents state of scientific evidence (including 
information from well-designed scientific studies). 



E0"d 28K-S22-202-6 01 tTO/bOd WOHd f0:8T f66I-IT-abW 



29 



Prohibits: 

Any labeling limitation on inclusion of "truthful and non-misleading information" 
concerning the vitamin, mineral, or other dietary properties of the dietary supplement; 
and 

o The Secretary from establishing a "prior restraint' on labeling of dietary supplement 
health claims. 

Requires manufacturers to provide 30-day notification to the Secretary before making any 
new dietary supplement health chums. (Prohibits the Secretary from imposing additional 
pre-market requirements for these claims, including requests for further documentation.) 

Section 5. Dietary Intake Standards 

Requires: 

o The Secretary to determine by regulation daily values for nutrients which reflect the 
daily intake necessary to "promote optimal health and minimize the risk of disease 
or other health-related conditions;" 

o Daily nutrient values to be no less than the RDAs established by the National Academy of 
Sciences and provides for use of current U.S. RDAs until the required regulations are 
issued; and 

o The Congressional Research Service, in consultation with the Office of Technology Assess- 
ment, to review existing scientific data and to conduct one or more studies to determine 
amounts of nutrients provided by diets recommended by USD A, HHS, CDC, NTH, and 
other authoritative public health organizations necessary to minimize risk of disease and 
other health -related conditions and to promote optimal health. 

Section 6. Appeal 

Permits recipients of FDA warning letters to appeal within 60 days of issuance; 

Prohibits the Federal Government from initiating litigation while the appeal is pending, 
unless the Secretary concludes there is an imminent health hazard; and 

Entitles warning letter recipient to bring action in U.S. district court regarding the letter's 
validity or to seek any other judicial review available if the appeal is not satisfactorily 
resolved. 



WTd 28E2-S2S-20Z-6 0± WTO/tOd WObd S0:BT PS81-11-HM 



30 



Section 7. Office of Dietary Supplements 

Amends Title IV of the PHS Act to require the Secretary to establish an Office of Dietary 
Supplements within NTH to: 

o Conduct and coordinate scientific research within NIH related to dietary supple- 
ments and the extent to which dietary supplement use can limit or reduce risk of 
certain diseases; 

o Collect and compile results of dietary supplement research; 

o Provide advice to NIH, CDC, and FDA on dietary supplement issues, including: 

1) Dietary intake regs; 

2) Dietary supplement safety; 

3) Health and disease-related claims; and 

4) Scientific issues related to dietary supplement labeling and composition; 

o Compile database of dietary supplement and individual nutrient scientific research; 

o Coordinate NIH dietary supplement funding; 

o Explore potential role of dietary supplements in improving U.S. health care efforts; 
and 

Promote scientific study of dietary supplements in maintaining health and preventing 
certain diseases. 

Authorizes $5 million for FY 94 and such sums as necessary for subsequent fiscal years. 

Section 8. Effective Date 

Establishes enactment date of legislation as effective date, except for Section 3 ("Dietary 
Supplement Labeling and Composition") which would become effective 18 months after 
enactment. 



S0-d S8E2-S22-S02-6 01 tHO/WCId WOMd S0:8T t>66;-TT-MdW 



31 

Mr. Schiff. And there is one other item. This bill, H.R. 1709, 
among other things, would say that the FDA may not — and I stress 
the word "not" — classify any dietary supplement or any ingredient 
of the kind specified as a drug solely because it exceeds the level 
of potency that the Secretary determines is nutritionally rational or 
useful. 

The concern is about classifying as a drug, meaning the require- 
ment of a medical prescription for the use of such items. 

Do you have any problem with that provision? 

Mr. Zeller. I am not aware of any current plans we have to re- 
classify any existing dietary supplement category as a drug. 

In the advanced notice 01 proposed rulemaking, we do summarize 
the task force report which made a recommendation to the Com- 
missioner that FDA consider regulating amino acids as drugs. But 
that is merely an internal recommendation and doesn't represent 
any official FDA position. But using potencies, I am not aware of 
any current plans. 

Mr. Schiff. Thank you, Mr. Zeller. 

I yield back. 

Mr. Towns. Thank you. 

Congressman Sanders. 

Mr. SANDERS. Thank you, Mr. Chairman. 

This whole area is generating a whole lot of emotional fervor, but 
it touches something very, very deep in our society; and that is a 
mistrust that goes beyond a dietary supplement. It goes, I think, 
to the medical establishment. Medicine really has the answers to 
some of the major illnesses facing our society. And as you know, 
there are studies indicating that more and more people are going 
beyond establishment medicine to look at solutions to their own 
health problems. 

So as I sit here, I jotted down, 50 years ago breast feeding was 
thought to be, by the established medical people, not only a dan- 
gerous thing, but women were actually urged not to breast feed 
their babies. The people who talked about nutrition were thought 
to be quacks. Even in medical school today, there is a reluctance 
to talk about nutrition. 

People talking environment and cancer are still on the fringe, al- 
though more formal, organized thought is being paid to that. Shock 
treatment and lobotomies were thought to be sensible ways of 
treating mental illness. 

So there is not enthusiasm all the time for conventional medi- 
cine. And I think that is what this whole discussion is about. 

So, I would like to ask you, Dr. Shank, how much are you involv- 
ing — or do you intend to involve those people who look at alter- 
native medicine, those people who espouse the benefits of dietary 
supplements in the decisionmaking process? 

Without exception, all of us want the FDA, I believe, to act 
against the frauds; and they are clearly there. No argument about 
that. But where you have the gray area, I think Mr. Zeller said 
what is safe; and we all agree. But who makes that determination? 
How much is the alternative health community going to be in- 
volved in those decisionmaking processes? 

Dr. Shank. It is going to be very important to us that we have 
a good dialog with all professionals as we move forward in the de- 



32 

velopment of these policies. I, too, have heard the concern that we 
are not paying proper attention to this group. And we do want to 
reach out and get the advice from all of those that can contribute 
to this process. 

I think it is important to recognize, in the final analysis, we are 
going to have to have a public record that will withstand the state- 
of-the-art science at the time that that record is developed. So we 
need their input. We need their contribution to help us arrive at 
those proper decisions because we have to have a record that dem- 
onstrates that rather than saying you should do this because I say 
so. We are very interested in reaching out to all of them. 

Mr. Sanders. You mentioned task force on dietary supplements. 
Who is involved in that task force? Did you go out to the alter- 
native health community? 

Dr. Shank. No, we did not. There was a conscious decision that 
the task force be made up only of government personnel. We have 
indicated our intentions of reaching out. 

We have gone out — relative to folic acid, where there are some 
complications, and we didn't approach the health claim alone. I am 
saying that we are modifying our approach on that. But the point 
is we went to an outside advisory committee for assistance, and we 
also announced our intentions to hold a symposium and to reach 
out relative to antioxidant vitamins and cancer. 

And I think you will see this more in the future, the role of the 
FDA, of trying to reach out to more of these groups as we attempt 
to build policies in the future. 

Mr. Sanders. You just mentioned a moment ago "state-of-the-art 
science." That was the expression you used. Are you aware that 
there are many, many millions of Americans who have profound 
concerns about the wisdom or the correctness of, "state-of-the-art 
science?" 

Dr. Shank. Uh-huh. 

Mr. Sanders. And it would seem to me that we do want to look 
out to the people — the Bill Moyer's Show dealt with acupuncture in 
China. You can't laugh these things off. Millions of Americans re- 
gard these ideas. Chinese medicine is not a joke. It has been prac- 
ticed for thousands of years. 

So I would hope, at the very, very least, at the least, that I have 
a question mark in my mind about the Richardson bill. We are 
looking at it, but I hope, at the least, that you begin to take seri- 
ously some of the thoughts that millions of Americans have with 
regard to alternative approaches to health care. 

Mr. Zeller. Mr. Sanders, can I add a couple of things? 

On the FDA task force, there was a full day devoted to an open 
public meeting where the task force heard from all interested par- 
ties from morning until night. And the record of the testimony that 
was established at that meeting played a very important role in the 
task force deliberations. 

But more generally, I think what you are talking about is access 
to products other than mainstream traditional medicines. What I 
am hearing you saying is "access." And in this very emotional de- 
bate, as you have described it, we sometimes confuse the issue of 
what should the standard be for labeling claims with the issue of 
access? 



33 

And it is important to state for the record that as Congress con- 
siders what the standard should be for health claims on dietary 
supplement labels, that labeling is separate and apart from the 
question of whether the products should be on the shelves in the 
first place? 

If we were to complete our June 18 rulemaking and say that the 
health claims standard for dietary supplements should be the same 
as for foods, namely significant scientific agreement, you must un- 
derstand that even though we reject a particular claim, the product 
stays on the shelf. The product can be sold. It just can't bear the 
claim. 

So access remains, assuming that the product is safe and should 
be on the shelf from a safety standpoint. If we assume safety, the 
product will be there. The only question is what kind of explicit 
claim can be made on the label. 

Mr. Towns. Thank you. 

We have been joined by Congressman Horn from California, and 
I yield to him at this time. 

Mr. Horn. Thank you, Mr. Chairman. I am sorry to be late, but 
I was testifying on the reauthorization of the economic develop- 
ment administration that is vital to my constituency and I suspect 
most of my colleagues. 

Some of these questions might have been asked. Let me start in 
with one directed to Dr. Shank. Has FDA discussed requiring vita- 
mins to be dispensed by a licensed pharmacist on the prescription 
of a licensed doctor? To what degree has that been discussed within 
FDA? 

Dr. Shank. Congressman, we have no plans to require that vita- 
mins be represented as drugs, either as OTC drugs or on a pre- 
scription basis, unless they are for that purpose, such as prenatal 
supplements. 

Mr. Horn. Has it been considered at all within FDA to require 
prescriptions for the sale of vitamins? 

Mr. Zeller. Mr. Horn, just a few weeks ago, I was sitting where 
Bill Layden is sitting, and I was on the receiving end of all of the 
letters, phone calls, telegrams, and mailgrams that Ted Weiss' con- 
stituents were placing because they had been told by someone that 
if FDA has its way you are going to need a prescription to get your 
vitamin C. It is completely untrue. 

But I know what it must be like to be on the receiving end of 
that intense level of questions from your constituents. It was not 
true, and it is not true today. It is a very strong tactic of getting 
a message to Congress, but it has made a lot of citizens angry un- 
necessarily. 

FDA has no intention of forcing consumers to go to a doctor to 
get a prescription for vitamins and minerals. 

Mr. Horn. FDA, at this point in time, has no such intention. The 
question was: Has it been discussed within FDA? 

Mr. Zeller. Not to my knowledge. 

Mr. Horn. I have forgotten if we take people under oath in this 
committee. In another committee I am on, we do. 

Mr. Towns. We do in this committee. 

Mr. Lake. Let me answer that question. I am Bob Lake. I have 
been at the Center for Food Safety now for 19 years, and I have 



34 

not heard a serious discussion about requiring vitamins and min- 
erals to be prescription drugs in at least the last 10 of those years. 
It simply has not happened. 

I think — let me clarify one other thing that I think may be a con- 
cern — underlying concern here too. There seems to be a 
misperception that if something is classified as a drug that that 
automatically means that it is a prescription drug. And that is not 
true. You can go into any drug store, of course, and buy over-the- 
counter drugs; and people do so everyday. 

The other point I would make, relative to your question, is — not 
since the Proxmire amendment, which prohibited us back in the 
1970's from making vitamins and minerals drugs based on their 
potency. That law effectively ended the argument. Regulation of vi- 
tamins as drugs simply has not gotten serious consideration since 
that time except, as Dr. Shank pointed out, those specialized prod- 
ucts such as prenatal vitamin formulations that are specifically for- 
mulated to be dispensed under a doctor's care to pregnant women 
and certain other similar kinds of products, but not the typical 
products that you buy in the drug store. 

Mr. Horn. In other words, if Linus Pauling wants to take 8,000 
units of vitamin C, he is free to do so? 

Mr. Lake. He or anyone else. FDA has never directed its regula- 
tions at consumers. Our regulation is directed at those who sell 
products, and our concern is always with either one of two things: 
Is the product safe? And the other one is: Is it properly labeled? 

Mr. Horn. Is there a division of labor within the Food and Drug 
Administration between the number of people devoted to, let's say, 
dietary supplement as a review process, versus the numbers de- 
voted to the more obvious examples of the review by the agency of 
various types of prescriptions that might be applied to AIDS, HIV, 
this kind of thing? 

What is the relative allocation of human resources in these 
areas? 

Dr. Shank. The resources for drugs certainly outweigh the re- 
sources that are available for premarket approval and these types 
of issues including labeling for food products, relative to food prod- 
ucts. 

There are more people that are available for the general food 
supply than there are for dietary supplements. 

But I can assure you that in the recent period of time, we have 
allocated more resources than traditionally existed because we 
think that proper regulation of the dietary supplements in the fu- 
ture and the fair regulation of these products is very important, 
and we have put additional resources to that effect. 

Mr. Horn. I gather your main emphasis is on false claims be- 
tween the dietary supplement community? Is that your main em- 
phasis? 

Dr. Shank. Earlier, I mentioned some concerns relative to tox- 
icity. We are reminded of the L-tryptophan amino acid. We have 
had some recent reports of toxicities from herbal products. There 
is a safety concern from certain products as well as the labels. 

Mr. Horn. Thank you. 

Mr. Towns. Thank you very much, Congressman Horn. 



35 

We have also been joined by Congressman Payne, and at this 
time I yield to him. 

Mr. Payne. Thank you very much. 

I certainly have received many communications and calls regard- 
ing this issue also, as have other members of the committee. And 
I am certainly concerned about some of the claims that we have 
seen on labels. For example, products that boast that the immunity 
of people who have a compromised immune system could be up- 
graded by some of these medications or over-the-counter products. 
You know, such exaggerated claims like this certainly need to be 
monitored so that the people who are most vulnerable certainly will 
not be victimized further. 

But we also have gotten some concerns about the — your proposed 
regulations, you know, governing nutrition labeling, nutrient con- 
tent, and the health claims from these dietary products. And there 
is a feeling that the FDA will unnecessarily restrict these dietary 
supplements, as the other persons have mentioned. 

We certainly need to be sure that there is balance in this ap- 
proach so that we don't overregulate and strangle ourselves when 
we still don't have enough beef inspectors and chicken inspectors. 
You know what I mean, which is also kind of serious. 

And so, I just wonder what degree of balance has gone into this? 
I understand you haven't gone out; you have done this internally 
inside the agency, which sometimes, I think, is the worst thing to 
do from what I have seen in the past. 

How will input or balance be guaranteed? 

Dr. Shank. Mr. Payne, I think that I agree with you, I think that 
we need to be fair; we need to be evenhanded; and the comment 
period obviously is still open. 

I want to underscore that we are talking here about an advanced 
notice of proposed rulemaking. That is a very preliminary stage in 
our development of the rules. We are truly seeking the input, the 
dialog with all interested parties. Following an ANPR — following 
this comment period, we would have to come back with another 
round of proposed regulations. So we are in the infancy, if you will, 
of establishing these. 

Regarding the comment that the amount of resources and the 
balance that we place with enforcing the regulations for dietary 
supplements, I don't believe you were here when I reported earlier 
that we have approximately 3,000 people in the field, FDA does. 
And we traditionally use only 15 to 20 of those people per year to 
look at the enforcement of dietary supplements. 

So our primary effort is dedicated toward getting this program 
right at the beginning through the regulatory process that we have 
under way. 

Mr. Payne. You know, I guess available consumer data indicates 
that supplements of these kinds are primarily used by better edu- 
cated people, upper income people, people who have access to pre- 
ventive medicine, people who are conscientious consumers. 

I wonder what you are trying to accomplish? Since you are mov- 
ing in this direction, how do you plan to talk about these products 
in the lower income, less educated, nutritionally deprived seg- 
ments, the people on public welfare, WIC, or food stamps? 



36 

I haven't seen anything in all the data that I have that there has 
been a notion of how to break into and educate that community to 
either tell them if these products are good and they should perhaps 
have some program to make them available or either tell them that 
they are not good and, you know, ensure — you know, suggest that 
they are warned about a product's use that they don't bother with 
it? 

I haven't seen anything currently that would say that inner cities 
or rural places or people who are currently health underserved are 
even in the mix. 

Dr. Shank. Mr. Payne, I want to make a couple of points in that 
regard. 

No. 1, nutrition education: We, as you know, are having a new 
food label on the traditional food; and we will have a new label at 
some point for dietary supplements. It is very important to us as 
a Nation that we educate the consumer on the proper use of that 
label so that they can better identify the foods and choose the foods 
for more adequate diet. 

The second point that I would make is relative to fortification. 
It is true that the supplements do not enjoy as wide an audience 
as could be helped by these products. And, therefore, as is the case 
with folic acid and the prevention of some of the neural tube de- 
fects, we are also considering changing the standards of our for- 
tification program where more traditional foods such as enriched 
bread could also carry those nutrients. 

So I think our answer is education, education to the general pub- 
lic, a better job of educating through some of our food assistance 
programs which USDA administers such as the WIC program. That 
will get right at the target group. And I know they are considering 
some enhanced education activities in that regard. 

And then we have to look at other opportunities that are avail- 
able to us such as fortification. 

Mr. Payne. Thank you. 

Mr. Towns. Thank you very much, Congressman Payne. 

On that note, are there dietary supplements that should be 
banned outright or have their use restricted by regulation? 

Dr. Shank. Only those supplements for which we have a safety 
concern. And we must deal with high potency amino acids. I am 
not saying that they should be banned, but we must deal with 
these. We must deal with some of these herbal products that con- 
tain concentrations of toxic materials at such levels as they present 
problems. But those are the only circumstances that readily come 
to my mind. 

Mr. Towns. How does FDA define significant scientific agree- 
ment? How does FDA determine that significant scientific agree- 
ment actually exists? 

Dr. Shank. How do we determine that? 

Mr. Towns. Yes. 

Dr. Shank. Very difficultly. We recognize that our interpretation, 
to date, relative to the significant scientific agreement has been 
controversial. It has been particularly controversial among those 
interested in the dietary supplement industry. I think that this is 
one of the most important — one of the more important issues that 



37 

we had to deal with during this regulatory process that we have 
embarked upon. 

It is true that we have held our proposal for health claims for 
dietary supplements to the same language, significant scientific 
agreement. But basically, if you would, let me say that these are 
FDA regulations, and we take full responsibility for them. 

But I would want to also share that they were not developed in 
a vacuum at FDA. The PHS the Public Health Service, was pro- 
vided an opportunity to participate in the detailed conclusions that 
were being drawn. The Deputy Assistant Secretary for Health led 
a major part of this initiative. The various units at NIH were in- 
volved. Two that come to mind were the National Cancer Institute 
and National Heart Lung and Blood Institute. The Centers for Dis- 
ease Control had their input. And the final analysis was the result 
of notice and comment rulemaking. 

Sure, FDA worked through those comments; but, again, we are 
trying to open that up. And we are trying to make the right deci- 
sions. And I am suggesting that you will hear more today about 
significant scientific agreement. It is a concern of ours. 

Mr. Towns. Is that the same as scientific consensus? 

Dr. Shank. No, it isn't. 

Mr. Towns. What is the difference? 

Dr. Shank. I think — I think that the consensus is a higher stand- 
ard, if you would. 

But your asking me those questions demonstrates the confusion 
that we have to work through. Consensus to me means more than 
a significant scientific agreement. 

Mr. TOWNS. Thank you very much. 

Any other comments or questions by members? 

Mr. Horn. I have one or two questions, Mr. Chairman. 

Health claims — FDA regulations refer to that language, as I un- 
derstand it. Now let's say a company has an article printed on nu- 
trition in the New England Journal of Medicine or any other sci- 
entific publication. It is a reputable figure in the field that has pre- 
pared this argument. 

My understanding is that if you take literally the health claim 
jurisdictional reference of FDA, that would be constituted as label- 
ing if the company distributed it around the country. Is that true? 

Mr. Lake. Mr. Horn, let me try to answer that. What FDA regu- 
lates are basically two things in this regard. One is the label itself, 
which is fairly clear — and we all have a good conception of that. It 
is the product with a piece of paper on it. 

Now, in addition to that, the Food, Drug, and Cosmetic Act has, 
at least since 1938, also prohibited false and misleading labeling. 
And that is defined in the act as material that accompanies the 
food in close association with it. The same applies to cosmetics. It 
is uniform across the products that FDA regulates relative to foods, 
drugs, and cosmetics. 

The scientific article that is published and perhaps distributed 
solely as an educational piece independent or separate and apart 
from any promotional scheme for a particular product is like all 
other pieces of printed material. It simply is not regulated by FDA. 

Also, FDA does not regulate media advertising. We don't regulate 
what goes on TV or what is printed in the newspaper. 



38 

So, again, what we are talking about in terms of what we regu- 
late is very narrowly constrained. And typically labeling relates to 
brochures that ordinarily would be handed out at the same time 
the product is purchased or right there on the counter. 

Now, the exact limits, of course, to some extent have been de- 
fined by case law. But, there is still this fuzziness. But I think the 
main point is that, FDA is not in the business of trying to regulate 
the general dissemination of scientific information. We couldn't do 
it even if we wanted to. And we have no such desire. 

What we are focusing on is the situation where somebody may 
take out of context a statement from a scientific study, particularly 
if it is a preliminary study, and then use it as part of the pro- 
motional material to induce people to buy a particular product. 

And that, we see — and the law itself sees — as really being no dif- 
ferent than actually having it specifically attached to the label. 
And, again, the whole point here is that we believe very strongly 
in freedom of choice. But if the choice is induced by false or mis- 
leading information, and that can include information that is taken 
out of context, then it is really a false choice. And that is what we 
are trying to prevent. 

Mr. Horn. Let me give a little more specificity. The New Eng- 
land Journal of Medicine is a jury journal. Most articles in there 
probably are articles that are sent out to various and sundry sci- 
entists and so forth to advise the editor as to whether they are rep- 
utable enough to publish in that distinguished journal. 

So we have one type of example where a company that perhaps 
makes a particular product sees an article that sort of justifies that 
whole product by legitimate scientists; it has gone through the jury 
process of the New England Journal of Medicine, and it simply dis- 
tributes it to everybody in the profession. 

As I hear your testimony, you don't have a problem with that. 
That is a matter of free speech. 

Mr. Lake. Again, the question becomes one of at what point does 
the statement in this article get really identified with a particular 
product. 

Under the law before NLEA, if you extracted a statement out of 
the New England Journal, particularly if it is taken out of context, 
if you put it on the label of a food, put it on your corn flakes or 
whatever — if as presented on that product it would be misleading 
because not all of the material is there, then that would have been 
a violation of law all along. 

Under the NLEA, Congress provided for putting claims on cereal 
boxes and other foods as well as on dietary supplements, but only 
so long as it met the standard, in the case of foods, of significant 
scientific agreement, and NLEA provided a process for getting a 
judgment on significant scientific agreement. It is a petition proc- 
ess that has just recently been put in place earlier this year. 

And so if that claim, that, is to be attached to the label or to be 
sold as an accompanying brochure is cleared through this process, 
then it is perfectly OK. If, at the other extreme, it is never con- 
nected to the product, that is none of our business. 

But under the law as it stands today, the most recent law passed 
by the Congress in this area, if you take language out of that arti- 



39 

cle and put it on a box of corn flakes and you have not gotten the 
claim cleared, then it is, per se, unlawful. 

Mr. Horn. What I am saying is they simply distribute the total 
article. Now, we have two choices; one, they can distribute it and 
send it as a matter of information and they don't even mention 
their product. You are saying no problem if they don't mention 
their product; they just distribute it. 

Mr. Lake. Again, it does depend to some extent on how that is 
done. If the product, if the display is put on the counter along with 
the product so that they are clearly being distributed together, then 
that would constitute labeling under the law, with a history going 
back for at last 50 years. 

Mr. Horn. You are saying even if they wrap that article around 
the product and distribute it with the product and you had to wade 
through 8,000 words to find it, you have jurisdiction and you would 
object to that? 

Mr. Lake. That would be labeling under the law and would have 
been, or has been, since 1938. 

Mr. Horn. So there really is not much free speech for articles 
from the medical community as far as FDA is concerned. 

Mr. Lake. Total free speech as long as you don't wrap it around 
a label and a product so that it is used for the express purpose of 
inducing the sale of that product. Then it becomes a question of 
whether it is false or misleading and/or whether it is an approved 
health claim or not. 

Mr. Towns. The gentleman's time has long expired. 

Mr. Sanders. 

Mr. Sanders. My last very brief question gets a little bit outside 
of this discussion and deals a little bit with emphasis on the part 
of the FDA. Can I ask you, Dr. Shank, or any of your colleagues 
there, in your judgment, are dietary supplements more of a health 
hazard for the American people than, say, Coca Cola, Twinkies, 
and potato chips? 

In other words, millions and millions of people use those prod- 
ucts. How many people we have heard, and I expect there are peo- 
ple, who are getting sick, perhaps, or ill as a result of dietary sup- 
plements, but in terms of emphasis, which, in your judgment, is 
more of a problem? 

Dr. Shank. I think that any of those that you mention can be a 
problem, junk diets, et cetera. Our concern is that we provide for 
the proper regulation of dietary supplements, and I have, on more 
than one occasion, mentioned today where we think the safety con- 
cerns relative to dietary supplements reside. 

So I don't want to pin one against the other. I think either can 
be bad, either can be very good. 

Mr. Zeller. If I could add to that, Mr. Sanders. No one in their 
right mind would say soda or potato chips are being purchased for 
their potential therapeutic value. 

Mr. Sanders. Not if you watch the Coca Cola ads. They do add 
a lot to your life. They spend hundreds of millions of dollars trying 
to convince us of that. 

Mr. Horn. My 9-year-old son might dispute that. 

Mr. Zeller. With that aside, there are hundreds, perhaps thou- 
sands, of dietary supplements out there that are being purchased 



40 

for their potential therapeutic value. And when something is being 
purchased not for its flavor or taste or aroma, but because it will 
prevent you from getting something, reduce your risk of getting 
something or help treat something that you already have, it raises 
a whole different set of questions about safety and labeling and 
that is really what has brought us here today. 

So I understand why you are asking your question, but let us 
keep in mind why we eat potato chips and why a lot of people are 
going to the health food store for their amino acids and herbs and 
some of the other products out there. 

Mr. Sanders. Thank you. 

Mr. Towns. Yield to Congressman Payne. 

Mr. Payne. Just a clarification. FDA has stated publicly that the 
vast majority of the supplements pose no safety or health threats, 
and this seems to be especially true for vitamins and mineral sup- 
plements. If this is so, then I am a little confused. Why is the FDA 
proposing to set potency limits on vitamins and mineral supple- 
ments and to require new safety procedures to justify the continued 
marketing of many products? 

I think before, Mr. Zeller, you said they would not take any prod- 
ucts off, they just could not say that they add to your life. What 
are your intentions as they relate to the products? 

Mr. Zeller. The advanced notice of proposed rulemak.ug dealing 
only with safety questions, not labeling questions, poses for public 
comment whether there is an interest in establishing safe upper in- 
take levels for vitamins. We are just throwing that out for the pub- 
lic to comment on. Is there interest in pursuing that from a safety 
standpoint. 

The Proxmire amendment in 1978 left the agency free to consider 
taking action on the potency of these products if there were safety 
concerns, and this advance notice of proposed rulemaking is about 
the safety of these products. And amongst the universe of issues for 
everybody to consider is should we look at a process that would es- 
tablish safe upper intake levels for vitamins. 

Mr. Payne. You know, it has been a long debate, I think for 
years and years, about vitamins. You can go to a physician and 
they say, take them if you want, I don't think they do anything; 
or you can go to another one and he says, I suggest that you take 
them every day, they are the greatest thing in the world. 

Is there any medical evidence — I hear the specific scientific 
agreement and specific scientific consensus and all that, but is 
there any kind of ongoing sense or agreement or movement where 
physicians, in general, where they stand as it relates to vitamins, 
as something good for you or something that really doesn't make 
much difference? 

Dr. Shank. Yes, there is a general movement. A case in point 
would be calcium and osteoporosis; folic acid and the prevention of 
certain neural tube defects; there is a continuing interest in dietary 
fiber and antioxidant vitamins. We are not there yet on all of these, 
but that is where the science is taking us, and it is leading to dif- 
ferent recommendations by physicians relative to influencing indi- 
viduals' diet and their health. 

Mr. Payne. How about just a general person, like a child, just 
to take this all-encompassing vitamin? 



41 

Dr. Shank. We don't have any data before us to say whether or 
not there have been changes in the physicians' practices, but from 
personal knowledge I know that a number of physicians do rec- 
ommend dietary supplements to young children, as an example. 

Mr. PAYNE. Thank the Chair. 

Mr. TOWNS. Thank you. Thank you very much. 

Let me thank all the members of the panel, Dr. Love, Mr. Lake, 
Dr. Shank, and Mr. Zeller for coming this morning. We appreciate 
your input. As you can see, it is an area that we have a lot of con- 
cerns about. We will also view the task force in terms of the rec- 
ommendations it has made and how FDA will ultimately imple- 
ment them. 

So thank you very much for coming this morning and thank you 
for your input. 

Dr. Shank. Thank you, Mr. Chairman and members of the sub- 
committee, we appreciate the opportunity to be here. 

Mr. Towns. Thank you. I would like to call the second panel, Mr. 
McNamara, senior partner, Hyman, Phelps & McNamara; followed 
by Mr. Silverglade of the Center for Science in the Public Interest; 
followed by Dr. Richard Johnston of the March of Dimes Birth De- 
fects Foundation; and followed by Ms. Stark of the New York State 
attorney generals's office. 

If you will take a seat at the witness table, we can proceed. It 
is the custom of the Government Operations Committee to ask that 
all witnesses who present testimony to this committee be sworn in. 
Please stand and raise your right hand. 

[Witnesses sworn.] 

Mr. Towns. Let the record show that the witnesses answered in 
the affirmative. 

Thank you very much. Please be seated. Let me begin by thank- 
ing you for taking time out of your busy schedules to be with us 
today to discuss this important issue. 

As I explained earlier, the full text of your written statement will 
be inserted in the record, and also the ranking minority member 
assured you that would happen. 

I ask that you summarize your statement in approximately 5 
minutes and, Mr. McNamara, why don't we start with you. 

STATEMENT OF STEPHEN H. McNAMARA, HYMAN, PHELPS & 
McNAMARA, P.C., ON BEHALF OF THE UTAH NATURAL PROD- 
UCTS ALLIANCE 

Mr. McNamara. Mr. Chairman, thank you. 

In view of your assurance, I will take this opportunity and I will 
not read at all for the record. I would like to point out who I am 
representing here, however, and then I will proceed, and I would 
like to, if I might, address some of the points that the committee 
raised with the FDA. 

I am Stephen McNamara. I am here as a representative of the 
Utah Natural Products Alliance. The UNPA is an association of 
companies in Utah that manufacture and distribute dietary supple- 
ments of vitamins, minerals, herbs, and other similar nutritional 
substances, both in the United States and internationally. They are 
very interested in this subject. They have been working together 
witn their senior Senator, Senator Hatch, but they have also been 



42 

working together with Members of the House, including Congress- 
man Richardson and his colleagues on behalf of his bill. They are 
very interested in legislation of the type that Senator Hatch and 
Congressman Richardson have introduced, and we believe such leg- 
islation is very important. 

Now, I would like to move from that generality to say, first, we 
have prepared a detailed written statement with citations and ex- 
amples which we hope will be helpful to your staffs as you get into 
this, and I am going to just avoid that completely and move di- 
rectly into some themes that I heard you gentlemen raise, and I 
would like to deal with those. 

I think I will, hopefully, have time to address three themes I 
think you should hear about today. One is safety, one is labeling, 
and a third, that FDA avoided mentioning, although it is encom- 
passed in every bill in Congress with this subject, has to do with 
companies getting judicial review of allegations from FDA that 
their products are in violation of law, and that is something we 
have to get to. 

But let's talk first about safety. FDA asserts that it is concerned 
only about rational safety-related concerns. Let's talk about a re- 
cent example where one can get some independent insight about 
what FDA believes to be rational safety-related concerns about 
products that they regulate. Let's talk about a dietary supplement 
of a substance called black currant oil. 

Black currants are the same substance used to make black cur- 
rant jam, for example. There has been a growing interest in this 
country, and elsewhere around the world, in the dietary properties 
of the oil expressed from black currant seeds because that oil pro- 
vides a substance known as gamma linolenic acids, which a num- 
ber of people are interested in and believe is useful as a dietary 
supplement. 

I am a lawyer, I am not a scientist. I cannot tell you about the 
merits of it as a scientist, but I do know I have heard a Nobel prize 
winner talk about the merits of it, and I can go into that if that 
becomes important, but let's talk about the substance itself. 

Under current law, FDA initiated a series of court cases against 
dietary supplements of black currant oil, and just this year these 
have finally gotten up to the U.S. Courts of Appeals in two dif- 
ferent circuits, the seventh and first circuits. Let's see what the 
Courts of Appeals had to say in these cases. 

First of all, if you want to talk about safety, there was no safety- 
related issue at all. "FDA has not shown," said the Seventh Circuit 
Court of Appeals, "that black currant oil is adulterated or unsafe 
in any way." We are talking about a product that presented, in 
fact, no real safety-related concern. But what did FDA do? They 
plopped on the product the allegation it was an unapproved food 
additive. Why? Because the oil was added to a gelatin capsule. 

Now, that made it, in FDA's mind, an unapproved food additive. 
And under that theory of law, as the Court of Appeals said, if the 
substance is deemed to be a food additive, it is presumed by law 
to be unsafe and therein becomes illegal until one gets a food addi- 
tive regulation of the kind the law originally conceived of being for 
chemical preservatives and things of that sort, but not for tradi- 



43 

tional basic foods and substances people want to sell as food prod- 
ucts in dietary supplement form. 

Both U.S. Courts of Appeals ultimately concluded that FDA was 
totally off the wall in asserting that these products were illegal, 
adulterated dietary supplements by trying to apply the unapproved 
food additives definition. And this is not my language. The U.S. 
Court of Appeals for the Seventh Circuit describes FDA's approach 
to dietary supplement safety as an "Alice-in-Wonderland ap- 
proach." This was a unanimous decision, seventh circuit, January 
27, 1993. The first circuit was a little more cautious in its phraseol- 
ogy and just called it "nonsensical." All right? 

Basically, it shows that while FDA can sit here and tell you that, 
in principle, it is only interested in going after unsafe matters, 
when you look at the way they have applied the law, they have 
gone after safe products and have tried to apply the unapproved 
food additive definition to them. We think that is an outrageous 
way to go, and the law needs to be changed to take away from FDA 
the possibility of asserting that a food substance, a safe food sub- 
stance in a dietary supplement, is an unapproved food additive. 

I had two other points I wanted to reach, but I see the little red 
light bulb. I will pass to my colleagues. I don't want to abuse my 
share here. 

Mr. Towns. Great. Thank you very much, Mr. McNamara. 

[The prepared statement of Mr. McNamara follows:] 



44 



FINAL TEXT 



Testimony 

of 

Stephen H. McNamara 

Hyman, Phelps & McNamara, P.C. 

Washington, D.C. 

Legal Counsel for 

THE UTAH NATURAL PRODUCTS ALLIANCE (UNPA) 

Salt Lake City, Utah 

at Hearing on 

"FDA's Regulation of Dietary Supplements" 



Hearing Before the Human Resources and Intergovernmental Relations Subcommittee of the 
House Government Operations Committee, U.S. House of Representatives, July 20, 1993 



Testimony 
July 20, 1993 



45 



Mr. Chairman and Members of the Subcommittee on Human Resources and 
Intergovernmental Relations: 

The Utah Natural Products Alliance (UNPA) appreciates the invitation to testify at this 
hearing on "FDA's Regulation of Dietary Supplements." UNPA is an association of Utah 
companies that manufacture or distribute dietary supplement products. These companies have 
been working closely with the senior Senator from their state, Senator Orrin Hatch, on behalf 
of appropriate legislation for dietary supplement products. UNPA strongly endorses the concepts 
underlying S. 784, the "Dietary Supplement Health and Education Act of 1993," which was 
introduced by Senator Hatch, for himself and Senators Reid and Murkowski, on April 7 of this 
year, although UNPA members hope for certain refinements in S. 784 during the legislative 
process. 

In addition, UNPA members greatly appreciate the interest and support of Congressman 
Bill Richardson of New Mexico and his colleagues, who have introduced H.R. 1709, also 
entitled the "Dietary Supplement Health and Education Act of 1993," and who clearly share with 
Senator Hatch, UNPA, and many Americans the desire to improve the current situation 
concerning regulation of dietary supplements. 

We have been asked by the Subcommittee's staff not to discuss today the particular 
provisions of these pending bills, but instead, to address ourselves to general principles 
concerning the regulation of dietary supplement products, and to identify particular types of 
regulatory provisions that either are, or are not, needed or appropriate for dietary supplement 
products. We are pleased to have the opportunity to do so. 



46 



Testimony SiJ 

July 20, 1993 



I. NEED FOR NEW LAW TO STOP FDA FROM TRYING 
TO IMPOSE "FOOD ADDITIVE" STATUS ON SAFE 
SUPPLEMENTAL FOOD SUBSTANCES 

UNPA believes that Congress should amend the Federal Food, Drug, and Cosmetic Act 
(FDC Act), 21 U.S.C. § 301 et seq., to make it clear that a food substance provided by a 
dietary supplement is not subject to regulation as a "food additive" by the U.S. Food and Drug 
Administration (FDA). This provision is needed because FDA has tried to prevent consumers 
from obtaining supplemental amounts of food substances that they want to consume by asserting 
that such substances are subject to the technical definition of "food additive" — with the result 
(FDA has asserted) that the substances may not be provided by dietary supplements without the 
prior issuance by FDA of a food additive regulation.^ 

UNPA believes food additive status for ingredients in dietary supplements should be 
reserved for chemical preservatives, solvents, processing aids, or other such technical or 
functional agents. 2 ' FDA should not be permitted to assert "food additive" requirements to 
prevent consumers from obtaining safe vitamins, minerals, herbs, or other similar food 
substances that they knowingly want to consume and to add to their diets by means of a dietary 
supplement. 

This is not just a theoretical concern. In recent years FDA has tried -- sometimes 
successfully — to deprive dietary supplement consumers of a number of food substances ~ 
including black currant oil, linseed/ flaxseed oil, evening primrose oil, co-enzyme Q10, chlorella, 



1/ It can cost from $1 to $2 million for a petitioner to prepare and pursue a food additive 
petition, and FDA approval of a food additive petition typically takes from 2 to 6 years. 
Kutak, Rock & Campbell, "FDA Safeguards Against Improper Disclosure of Financially- 
Sensitive Information: The Product Approval Centers," Final Report (November 14, 
1991) at 162; 33 Food Chem. News 67 (November 4, 1991). 

2/ Indeed, these kinds of additives are often not used at all in dietary supplements. 



Testimony 
July 20, 1993 



47 



and even orotic acid (a substance found in milk) by arguing that the substances - food 
substances, desired by consumers in dietary supplement form - were "food additives." 

Indeed, in the recent past FDA even suggested that compounds of chromium were 
unapproved food additives and thus illegal 2 ' when added to dietary supplements, even though it 
was clear that chromium is (1) a nutritionally essential mineral, (2) extremely safe (in the 
trivalent form commonly used in dietary supplements), and (3) not present in optimum amounts 
in all American diets.- (This year, after Senator Hatch had spoken out on the floor of the 
Senate in 1992 about FDA over-regulation of chromium supplements [Congressional Record, 
S. 7983, June 11, 1992], FDA implied that it was no longer so concerned about chromium 
[58 Fed. Reg. 2212, 2170, January 6, 1993], but there is no guarantee that FDA will not revert 
to its former attitude with respect to this essential nutrient.) UNPA believes that FDA should 
not be allowed to prevent consumers from obtaining supplements of chromium or other safe 
supplemental food substances by asserting that such substances are "food additives." 

I have had a striking personal experience with what I believe is FDA misuse of the food 
additive definitive in the case of dietary supplements. This concerned evening primrose oil. A 
few years ago, I accompanied Sir James Black, the highly respected British physician-researcher 
(who has won the Nobel Prize for Medicine), to a meeting with senior personnel at the FDA 
Center for Food Safety and Applied Nutrition. At that time, Sir James wanted to explain to 
FDA personnel why he believed that dietary supplements of evening primrose oil were both 
clearly safe and useful. In what was one of the most surprising and disturbing meetings that I 
have ever attended at FDA, Sir James was not allowed to explain to FDA personnel why he 
believed evening primrose oil was safe and appropriate for supplementation; instead, he was told 



2/ E.g., see 56 Fed. Reg. 60382 (November 27, 1991) ("Dietary supplements of . . . 
chromium. .. are not permitted"). 

4/ E.g., see National Academy of Sciences, Recommended Dietary Allowances, 10th ed. 
1989, pp. 241-243. 



48 



Testimony ^J 

July 20, 1993 



that FDA would not permit such a presentation and that the agency had already decided that 
evening primrose oil was an "unapproved food additive" and should not be sold as a dietary 
supplement. 

The extent of FDA's subsequent determination to eradicate all dietary supplements of 
evening primrose oil from the United States market has also truly surprised me. The most 
recent (1993) FDA Annual Awards Ceremony provides some instructive insight in this respect: 
At this ceremony the FDA Commissioner presented a special award to more than 60{}.) FDA 
personnel for pursuing regulatory actions against evening primrose oil. (See Attachment A.) 
Note that this crusade was taken against a product that I understand is readily available, with a 
substantial record of safety, to the general public in most of the rest of the modem world ~ 
including, for example, in Canada, Great Britain, Germany, Scandinavia, and Israel. Why 
should FDA be so determined to deprive American citizens of such a supplemental food 
substance that they want to consume? 

I am a lawyer and not a scientist, so I cannot, of course, speak as an expert about safety. 
However, FDA assertions that there are safety-related concerns about dietary supplements of 
evening primrose oil at reasonable potencies appear to me to be incredible. I have heard Nobel 
Prize-winner Sir James Black express just the contrary view; and, as noted above, the substance 
is widely available with a substantial record of safety in other sophisticated nations. The fact 
that FDA would give a major award to its personnel for preventing American consumers from 
obtaining a dietary supplement that is readily available elsewhere in the nodem world is both 
instructive about FDA's attitude concerning dietary supplements, and, I believe, disturbing. 

It is important to note here that preventing FDA from regulating food substances in 
dietary supplements as "food additives" would not deprive FDA of ample authority to protect 
consumers from unsafe products. Section 402(a)(1) of the existing FDC Act, 
21 U.S.C. § 342(a)(1), would continue to apply to dietary supplements. This section prohibits 
a food (including a dietary supplement) from bearing or containing any "poisonous or deleterious 



Testimony 
July 20, 1993 



49 



substance which may render it injurious to health." Under this section of the FDC Act, 
however, FDA must at least have some realistic basis to believe and show that a food substance 
is poisonous or deleterious and "may" render a product injurious to health before the agency can 
deprive consumers of foods that they want to purchase and consume - and that is just as it 
should be in a free society. 

There is another point that UNPA wants to mention here because it should be of special 
interest to the Subcommittee -- since it concerns the matter of adherence by a regulatory agency 
to laws enacted by Congress. 

One of the problems that the dietary supplement industry faces when FDA asserts that 
an ingredient in a dietary supplement is an "unapproved food additive" is that FDA has 
interpreted the law in such a manner that, in most circumstances, such an assertion by FDA 
becomes a necessarily-self-fulfilling prophecy. In general, FDA asserts that the only way for 
the proponent of such a substance to avoid food additive status, and illegality, is to show that 
the substance is "generally recognized as safe" ("GRAS") ~ but FDA then asserts that if its 
experts state that a substance is not GRAS, then, as a matter of law, the substance cannot be 
"generally recognized" as safe and therefore must be deemed to be a food additive. E.g., FDA 
asserts that once a court is presented with affidavits by FDA witnesses stating that a material is 
not GRAS, there is not even any reason for the court to hold a trial on the subject, and that 
summary judgment should be granted for FDA. 

We raise this matter here because such an argument by FDA - although it may meet with 
favorable acceptance in a court that does not particularly want to hear a long trial involving a 
battle of scientific witnesses who disagree about GRAS status - is, UNPA believes, in flagrant 
disregard of the interpretation of the food additive definition that FDA conveyed that it would 
abide by when the Food Additives Amendment was enacted in 1958. At that time, the 
representatives of the Department of Health, Education, and Welfare who testified for FDA 
before Congress about the proposed legislation explicitly stated that no matter what definition 



Testimony 
July 20, 1993 



50 



of "food additive" was adopted, in an enforcement action the burden would be on FDA to prove 
that a substance was not GRAS! (See Attachments B and C.) Current FDA practice essentially 
renders that testimony a nullity. Instead, FDA argues that the burden of proof is on anyone who 
disagrees with FDA to prove that a substance is GRAS, and that a substance cannot be GRAS, 
as a matter of law, if FDA says it is not. FDA's ability to manipulate the burden of proof and 
the meaning of the food additive definition in this respect is one more reason why the dietary 
supplement industry needs a clear statutory exception from food additive status for food 
substances provided as dietary supplements. 

n. NEED FOR EXPLICIT LEGISLATIVE RECOGNITION THAT 
LABELING FOR A DIETARY SUPPLEMENT MAY PROVIDE 
TRUTHFUL INFORMATION WITHOUT FDA PRECLEARANCE 

As Senator Hatch observed when the Nutrition Labeling and Education Act (NLEA) was 
passed in 1990, "By their very nature, the dietary supplements must be marketed so that the 
consumer is informed of the health or disease-prevention benefits that may be conferred." 
Congressional Record, S. 16611 (October 24, 1990). Nevertheless, since passage of that Act, 
FDA has repeatedly tried to impose severe restraints on the freedom of dietary supplement 
manufacturers efficiently to provide truthful health-related information in labeling. 56 Fed. Reg. 
60537, 60583 (proposed 21 C.F.R. § 101.14(a)(1)) (November 27, 1991); 58 Fed. Reg. 33700, 
33714 (proposed 21 C.F.R. § 101.14(a)(2)) (June 18, 1993). The dietary supplement industry 
needs enactment of legislation that clearly permits dietary supplement products to include in their 
labeling truthful information, including truthful information about the physiological properties 
or other health-related aspects of the products. 

Of particular concern here is the matter of a prior restraint on free speech, which should 
be regarded as anathema by Americans: FDA has repeatedly proposed regulations that would 
not allow truthful health-related information to be included in labeling for dietary supplements 
until after FDA first issues a final regulation approving the information ~ a process that can be 



51 



Testimony UnJ 

July 20, 1993 



expected to take years to complete. 56 Fed. Reg. 60537, 60563 (November 27, 1991); 58 Fed. 
Reg. 33700, 33714 (June 18, 1993). 

Let us be very clear here that UNPA is not arguing that companies should be free to 
make false or misleading claims. If a labeling claim is made that is false or misleading, or the 
claim otherwise violates a proper legal standard, FDA already has, should have, and would 
continue to have, ample authority to take action against the product, as a "misbranded" food. 
21 U.S.C. § 343. FDA can initiate a civil seizure action, an injunction action, or a criminal 
prosecution in response to the marketing of a misbranded dietary supplement, 21 U.S.C. §§ 331- 
334, or it can request a recall of the product. 21 C.F.R. §§ 7.40-7.59. However, UNPA 
strongly believes that a dietary supplement distributor should not be required first to obtain FDA 
permission, including the issuance of a new regulation, before the company may begin to 
provide nutrition-related information in labeling that the company is prepared to defend in court, 
if necessary, as truthful, not misleading, and supported by valid scientific evidence. Petitions 
to FDA to issue regulations can be extremely time-consuming and costly to prepare, and it 
typically takes FDA years to issue a new regulation. Labeling information about food substances 
should not be subject to such burdensome and delaying prior restraints. (Furthermore, 
enforcement convenience for FDA should not be given priority over freedom of speech!) 

The extent to which FDA has been willing to go to try to prevent dietary supplements 
from providing truthful and nonmisleading information in labeling is instructive here. Let's 
consider just three examples: 

A. Nutrition Newsletters 

FDA regards a company newsletter that reviews the recent scientific literature on health- 
related effects of nutrients as "labeling" for company products that contain those nutrients. 
Under the terms of FDA's NLEA regulations, such a newsletter, as "labeling," could not be 
published without the company's first obtaining FDA approval (by means of the issuance of a 



Testimony 
July 20, 1993 



52 



new regulation) for any report in the newsletter about a study that would link a nutrient to a 
health-related condition.-' 

The pragmatic "bottom line" of all of this is that, it appears, FDA's intentions for 
regulating the labeling of dietary supplement products would effectively prevent a company even 
from issuing a regular, timely newsletter that provides a truthful and nonmisleading review of 
the recent scientific literature concerning nutrients that the company sells. 

B. Labeling Statements About Evolving Science 

In the course of FDA's rulemaking proceeding on whether to allow health-related claims 
for omega-3 fatty acids in food labeling, at least one manufacturer filed comments with FDA 
in which it asked that food companies be permitted to make a truthful and nonmisleading, 
balanced statement in labeling about the nature and extent of evolving knowledge concerning 
possible benefits of fish and omega-3 fatty acids in the diet. The model labeling statement that 
the company's comments proposed reads as follows: 

There is considerable scientific interest in the subject of whether 
fish, or certain nutritional substances found in fish, including 
omega-3 fatty acids, may, when included in the diet on a regular 
basis, reduce the risk of coronary heart disease. At the present 
time, there is no established consensus that omega-3 fatty acids 
definitively have such an effect, but a number of researchers 
believe that such a relationship may exist, and research is 
underway to obtain further information. 

(Comments by Zapata Haynie Corporation, dated February 20, 1992, filed in FDA Docket No. 

91N-0103.) 



5/ Furthermore, it appears that FDA would probably not be willing to issue a regulation 
approving such a newsletter at all because the recent scientific literature, even if 
truthfully reported, would probably not yet have reached the state that FDA would regard 
as "significant scientific agreement" about the matters described therein! 



Testimony 
July 20, 1993 



53 



So far, at least, FDA has refused to permit a statement of this type about omega-3 fatty 
acids to be used in food labeling — in part, it seems, because the agency appears to be opposed 
to any labeling at all, even truthful labeling, about evolving health-related knowledge that has 
not reached the point of (what FDA regards as) significant scientific agreement that a nutrient 
will inhibit a disease (as distinguished from significant scientific agreement about the current 
state of evolving knowledge concerning whether a nutrient may have that effect). See generally 
58 Fed. Reg. 2478, 2682 (January 6, 1993). I am a lawyer and not a scientist, but I understand 
from some highly-qualified experts that the model labeling quoted above is a fair and reasonable 
brief summary of the current state of scientific knowledge and opinion on its subject. It saddens 
me to realize that my government has tried to put in place a new requirement of law that would 
prevent a food company from being able to provide truthful and balanced labeling information 
about evolving scientific knowledge. 

If a company wants to make such a statement in labeling, on the premise that the 
statement is truthful and not misleading, and the company is prepared to defend the scientific 
validity of the statement, and is willing to assume the risk that FDA might bring regulatory 
action against the company in court if the agency should conclude that the company has made 
a false or misleading statement, why should the company not be free to make such a statement 
on its own responsibility? UNPA believes that a company should notneed to wait, first, for the 
wheels of government at FDA slowly to grind out concurrence that such a statement is truthful 
and not misleading, and then, for FDA to publish an authorizing regulation (which, inevitably, 
takes FDA years to accomplish) before such a statement may be made in labeling. Such prior 
restraints on speech should not be tolerated by Congress. 

Moreover, UNPA believes that companies should not be subjected to a regulatory system 
where (as appears to be the situation here) FDA may even acknowledge that a proposed labeling 
statement is truthful, but nevertheless refuse to permit the statement because the agency takes 
the position that the only health messages it will approve for use in labeling are ones where the 
described nutrient has been proven to have disease-preventive benefit. Why should a company 



54 



Testimony 



July 20, 1993 



be denied the freedom to provide a truthful summary of evolving scientific knowledge about 
whether the nutrient may have such benefit? Is this the kind of law - restriction on truthful 
speech about evolving scientific knowledge ~ that we want to have in a free society? What kind 
of country are we creating for ourselves in the future? 

UNPA believes that, in addition to the mandatory basic label information (e.g., statement 
of identity, net quantity of contents, list of ingredients, and name and address of the responsible 
company), and subject to the need to conform label statements to any pertinent definitions of 
terms that have been established by law (e.g., in a valid FDA regulation), in general, (1) any 
truthful and nonmisleading statement should be allowed, so long as it is not a drug claim (and 
we do not believe the model statement proposed by Zapata Haynie, for example, amounts to a 
drug claim), (2) such labeling should be subject to government policing and enforcement actions 
for violations (e.g., for false or misleading statements) but not to preclearance, and (3) a 
regulatory process that would chill truthful speech should not be tolerated. 

C. Labeling Statements About Quantitative Content 

As a third example of the extent to which FDA has been willing to go in trying to 
prevent dietary supplement companies from providing even truthful information in labeling, 
consider the fact that recent FDA regulatory correspondence has actually told some companies 
that they should not state in labeling how much of a supplemental substance is provided by a 
tablet. For example, in correspondence issued on July 16, 1992, FDA told one company that 
a label text that the company had proposed to FDA was improper because "[i]nositol[,] choline 
bitartrate, para-aminobenzoic acid, citrus bioflavonoids and betaine hydrochloride are declared 
in milligram amounts on the label of this vitamin and mineral tablet." (See Attachment D.) 
FDA did not want the company to tell its customers how much of each of these substances was 
present in the product! 



Testimony 
July 20, 1993 



55 



Do we realty want the public's limited resources being spent by FDA on preventing a 
dietary supplement company from truthfully telling how much of a substance is present in a 
dietary supplement? 

All of the foregoing examples underscore a continuing concern of the dietary supplement 
industry. The industry needs to be able to provide truthful and non misleading information to 
its customers. UNPA is full-willing for the industry to be held to a high standard of truthfulness 
in providing information, but companies should not be required to obtain FDA issuance of an 
approving regulation before using new labeling. Such a prior restraint on free speech would 
delay, or effectively prevent entirely, the communication of truthful information about products, 
and it would also build the size of an additionally-expensive regulatory bureaucracy. 

We emphasize that the desired legislation would not authorize false or misleading claims. 
Whenever FDA believes that a false or misleading claim has been made in labeling for a dietary 
supplement product, or that a claim has been made that goes so far in providing health-related 
information that the product should be deemed to be a drug, the agency has ample power to take 
action in court - under the authority that it already has under existing law — to obtain seizure 
and condemnation, or to obtain an injunction, or to pursue criminal prosecution — subject to the 
burden, which FDA properly should bear, to show that the product is indeed in violation. 21 
U.S.C. §§ 331-334, 343(a)(1). The federal courts, including even the United States Supreme 
Court, have affirmed FDA's power to stop improper claims for dietary supplements under 
existing law by initiating seizures or taking other punitive action when such claims have been 
made. E.g., Kordel v. United States, 335 U.S. 345 (1948) (criminal prosecution for improper 
claims). Accordingly, if FDA should present to this Subcommittee some extreme or gross 
examples of products that appear to bear false or misleading claims, or improper drug claims, 
FDA should be told to exercise its existing authority to take regulatory actions against 
improperly-promoted products; but it should not be allowed to set in place new rules, as now 
proposed, that would require honest distributors of dietary supplements to obtain a new 
regulation from FDA approving each new health-related statement before the statement may 



Testimony 
July 20, 1993 



56 



appear in labeling. Such a prior restraint on truthful speech is unnecessary and inappropriate. 
An agency that has not properly exercised its ample existing authority to take action against 
wrongdoers should not be given new authority that would have the effect of restraining free 
expression of truthful information by honest citizens as well as the wrongdoers. 

EH. NEED TO BE ABLE TO OBTAIN JUDICIAL REVIEW 
OF FDA WARNING LETTERS 

UNPA's third legislative goal is a simple request for fundamental procedural fairness in 
FDA regulation. FDA's primary form of initial regulatory action against allegedly improper 
dietary supplement products is the issuance of a "warning letter." Such a letter, usually 
addressed to the president of a company, is put on public display by FDA; and it routinely 
asserts that a particular product is in "serious violation" of the law ~ either because the product 
allegedly bears false or misleading labeling, or because it allegedly contains an "unapproved 
food additive," or because it allegedly bears labeling that constitutes an unauthorized drug claim. 
The warning letter also routinely threatens an action in court against the product or company. 
These letters are promptly put on public display at FDA headquarters, and they are frequently 
the subject of reports in the press or other media. 

Such a warning letter can have a devastating impact upon a company, causing the 
business community, customers, stockholders, and others to believe that the company is in 
"serious violation" of law and in danger of an enforcement action in court. 

If the points raised by FDA in a warning letter have merit, usually the addressee 
company will promptly take corrective action. However, in circumstances where a company 
believes that FDA's letter is in error, a most unreasonable situation currently applies. Even 
though the letter has been made public by FDA and states to the world that the agency has 
concluded that the company is in serious violation of law, nevertheless, FDA will not agree that 
the company can obtain judicial review of the merits of such a letter in court. Instead, FDA 
argues that such a letter is not technically "final agency action" (because the agency might 



57 



Testimony tbJ 

July 20. 1993 



possibly change its mind - although the letter contains no hint of that). The effect is that a 
dietary supplement company can receive from FDA a formal public warning telling the company 
that it is in serious violation of law, and demanding that it cease marketing a certain product, 
and yet FDA will not allow the company to obtain judicial review of the merits of the assertion. 

Such a situation is fundamentally unfair. FDA should not be allowed to issue threatening 
and disparaging warning letters, which are made available to the press and the public generally, 
without having the warning letter be subject to judicial review. UNPA believes that legislation 
is urgently needed to authorize a company to obtain judicial review of any public warning letter 
that is issued to it by FDA, asserting that the company is in violation of law. 

IV. CONCLUSION 

UNPA hopes the foregoing comments are helpful. We will be pleased to try to answer 
any questions you may have. 



***** 



58 



Ce c« ** ony 



R-o* ro. *m 



COMMISSION! «"S SFTOAL CITATION (I 



Evening Primrose Oil Litieation Team 

for outstanding performance in the investigational and evidentiary seizure proceedings 
concluding EPO litigation m California and Maine. 

From the Centers for Drug Evaluation and Research, and Food Safety and 
Applied Nutrition, the Atlanta, Boston, Buffalo, Chicago, Denver, Kansas 
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the General Counsel: 



S 



Marvin G. Appleton 
A. Joel Aronson 
R. Daniel Benz, Ph.D. 
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Robert A. Chamberlin 
Isabel S. Chen, Ph.D. 
Timothy J. Couzins 
Philip 5. Derfler 
Jane E. Easttey 
Ralph A. Erickson 
Anne Fabiszewski 
David Firestone 
Donald G. Gordon 
John D. Harris 
Sara H. Henry, Ph.D. 
S. Steven Hotta, M.D. 
Hilrje Irausquin, Ph.D. 
Stanton W. Johnson 
James M. Kewley 
Camilla K. Kintner 
Jean Knight 
Charles J. Kokoski 
Michael R. Kravchuk 
Leslie Kux 
Margaret M. Laski 
Ronald R. Laski 
Marijane C. Lawson 
Lawrence J. Lin, M.D. 
Shelly L. Maifarth 
Barbara Marcelletti 
Gerad L. McCowin 

Amanda B. Pedersen 

Chief Mediator and Ombudsman 

r outstanding skills and exceptional performance as the Food and Drug Administration 's 
Chief Mediator and Ombudsman. 



Francis G. McNemey 
Daniel L. Michaels 
Edith D. Miller 
Richard C. Nelson 
Louisa Nickerson 
Frances V. Noyes 
Janice F. Oliver 
Mary K. Pendergast 
Richard H. Pent a 
Antoinette M. Pusaher 
Ruth E. Rubino 
James P. Reavey 
Robert J. Reina 
Peter A. Salsbury 
Emil G. Siegmund 
Manjeet Singh 
Solomon Sobel, M.D. 
John J. Stamp 
Linda M. Stewart 
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Donald W. Stresser 
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Michael D. Wirth 
Edward J. Wojtowicz 



4,1 IMAA**** •* ^fl 



t^fZh. 



«J»>4UA*-Ut f****OWOr*£. 






59 

VOL. 13 LEGISLATIVE HISTORY OF THE FOOD. DRUG & COSMETIC ACT 



(Up 



FEDERAL FOOD, DRUG, AND COSMETIC ACT 

Jht'c '"^CHEMICAL ADDITIVES IN FOOD) 

'^V s 

'i HEARINGS 

BEFORE A 

SUBCOMMITTEE OF THE 

COMMITTEE ON 

INTERSTATE AND FOREIGN COMMERCE 

HOUSE OF REPRESENTATIVES 

EIGHTY-FOURTH COXGRESS 

HECOXT) 8F.SR10N 



H. R. 4475 

A BILL TO PROTECT TUE PVBUC HEALTH bt AMENDING TUB 

FEDERAL FOOD. OBl'G. AND COSMETIC ACT SO AS TO 

PROVIDE FOB TOE SAFETY OF CHEMICAL 

ADDITIVES LN FOOD 

H. R. 7605, H. R. 7606, H. R. 8748 

BILLS TO PROTECT THE PCBUC IIEALTH BT AMEXD1NO THE 

FEDERAL FOOD. DBDO. AND COSMETIC ACT TO I'UOBIBIT 

THE L'SK IN FOOD OF NEW FOOD ADDITIVES WHICH 

HAVE NOT BEEN ADEQUATELY TESTED 

TO ESTABUSO THEM SAFETY 

H. R 7607, H. R 7764, H. R 8271, H. R. 8275 

BILLS TO AMEND THE FETERAL POOD. DKCG. AND COSMETIC ACT 
FOR THE PROTECTION OF THE I'l'llLIC HEALTH BY PRO- 
HIBITING NEW >-CX>r> ADDITIVE8 WHICH HAVE NOT 
KEEN ADEQUATELY PRETESTED TO ESTABLISH 
TUE1R SAKE USE I'NDEX THE CONDITIONS 
OF TUEIR INTENDED USE 



JANtAUY 31. FEBUUABT 1. 2, 3, AND 14. IBM 



Printed for the one of the Committee on luleratate and Foreign Commerce 

DEPARTMENT OF 
IEALTH, EDUCATION, AND WELFARE 

UNITED STATES ^Q g jggg 

GOVERNMENT PRINTING OFFICE " ww " ■•*«#»» 
■nm WASHINGTON : 1»M LIBRARY 

LAW COLLECTION 



ATTAdNMedT 

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60 

VOL. 13 LEGISLATIVE HISTORY OF THE FOOD, DRUG & COSMETIC ACT 

226 FEDERAL FOOD, DRUG, AND COSMETIC. ACT 

must uphold the finding of the Administrator. You could change 
that act in many other fields, and perhaps make it work. But to 
select this highly technical field as on innovation, as a departure 
from the administrative act, it seems to me would be unwise. If we 
are going to experiment and try to improve it — and I think we can 
improve the administrative act — I much prefer to try on something 
else, and something that is not sc highly technical and does not involve 
the safety of so many people. 

There is one question here about this standard that troubles me. 
As I interpret the act, the standard of whether a man has obeyed the 
act or not — the test whether has has violated a criminal statute — is 
not whether the additive is safe or not safe. The test is whether it is 
generally recognized by the experts to be safe. 

If this were a purely simple matter, there might be some justifica- 
tion for that sort of a test But where a man is put in jeopardy, it 
seems to me that he is entitled to some standard that is much safer 
and much more certain than that. In order to determine whether he 
is committing a violation of the penal code, be has to pass on the 
question of whether the experts generally recognize. 

Mr. GoorancH. YeSj sir. 

Mr. Dees. He goes into the field of opinion and conflicting opinion 
and highly technical matters. I just don't think that is good, even 
though it is in tne Drag Act. I cant believe that is good legislation. 
I am wondering why we simply don't make the test the safety of 
the matter. Then he can certai nly make his decision. He is a manu- 
facturer. He has his experts. Whenever he makes his decision, then 
he will have to accept the consequences of it I am wondering what 
difference that would make if we substituted and changed that lan- 
guage and struck out the "generally recognized." 
(^^ JW ^fr^ooDRicii. We have in general language "generally accepted," 
^feA ^^^^ because (ReTommittee over the rears has never been willing to giTe 

** the Food and Drug Administration the authority to make a list to 

specify which products are in and which are out. This is what has 
y l«en called here an objective standard. 

A We have llie burden 1 no rnc^ fr ftpw this bill irfyf nf p|-nvinc- that 

/ a£ jcTTsTioT^; iiiy reco sized as s afe among. exper ts in th e 

"T^eTus assume that this bill came out as we recommended it and 
company X had a chemical which had not been adequately tested, 
we thought it was not generally recognized as safe, the applicant 
thought it was generally recognized as safe. Jjjejy^jnjdjjavethe 
burdenofcoinfljjo^ojgurt; to seize, prosecute, or enjoiny irove that 
[act, that it was not generally recogw-erl n« snf». 

»TeTu7veinTnisiooJ7ndarugTaw some general language. "Pre- 
pared under unsanitary conditions," "if it consists in whole or in 
part in filth," "if it is a poisonous or deleterious substance which may 
be injurious," all those generalities have been to the courts, and we 
have not had difficulty with vagueness knocking down the law. We 
have been singularly successful, I think. 

Mr. Dies. Under the present law, what happens if a man does put 
on the market — I am not talking about civil Lability, but criminal — 
a deleterious substance, something that causes great damage. Can 
he be criminally prosecuted I 






739" 



61 

FOOD ADDITIVES 



HEARINGS 

urois ▲ 

SUBCOMMITTEE OF THE 

COMMITTEE ON 

INTERSTATE AND FOREIGN COMMERCE 

HOUSE OF REPRESENTATIVES 

EIGHTY-FIFTH CONGRESS 

ON 

BILI.S TO AMEND TOE FEDERAL FOOD, DBCG. AND 

COSMETIC ACT WITH RESPECT TO CHEMICAL 

ADDITIVES IK FOOD 



JULY 13. 1«. IT. IS. 10. 2!. 23. M, ACGLST 8. 7, 1957. AND 
APRIL 10. 1953 



Printed for the ose of the Committee on Interstate end Foreign Commerce 




UNITED STATES 

GOVERNMENT PRIKTIXO OFFICE 

WASHINGTON : 1M* 



163 



ftrrac Hne*IT 

c 

see P. 4SS (*n> 



62 



VOL. 14 LEGISLATIVE HISTORY OF THE FOOD. DRUG & COSMETIC ACT 



FOOD AUIMTIVES 455 

courage the adoption of reasonably uniform laws. We need all the 
help they can give in controlling chemical additives, for the task is so 
big that combined Federal-State-city interest is imperative. 

Last year tlie State of Utah enacted a new food, drug, and cosmetic 
law that contains an approach to the control of chemical additives 
not too different from the basic principles in some of the bills you are 
considering. The State of Xew York is considering new additives 
legislation now. New York City is considering a revision of its 
sanitary code with respect to food additives. And we understand 
that food-law enforcement officials of other States are considering the 
steps they should take to deal with residues of additives. If the Fed- 
eral Government fails to enact legislation that can servs as a guide, 
the result may be the adoption of varying methods of State and local 
control. 

In conclusion, the problem, tlie real hazard of the use of inade- 
quately tested chemicals in food is very clear and is with us today. 
It is not, as some of the testimony last summer suggested, merely a 
theoretical problem. Inadequately tested chemicals are being used 
in food today and their use constitutes a renl hazard to the public 
health. 

(The information referred to follows:) 

Sn PrioibtTAt Stat i.mtnt of jiie U»t abt.mext"» Vhw i to Acc ompakt Statc- 

" nIHt ■■. r i . ' A l .r! * I 1 ' I.AKHJEU I f f i CnL.UIUL .'UI I I1UHI UliyU ' lU 1 

i. scon: or THE lccihlatio.x 

(«) Diflniliv* <// "cAnxHul tirfdllice" 

Tbe witness for the Grocery Manufacturers Assoeiailnu questions tbe defini- 
tion of "chemical additive" suggested in tbe administration bill. He inin: 

The food additive definition uuder review U prlnci|>uliy obscure, because of 
It* governing 'generally recognized' clause" 

Tbe »o-tiillcd generally recognized cluo«e here referred to Is tbe provision 
1 1 1 -. lines is- Hi under which ■ >ub*tauce which otherwise would be re- 
garded as a chemical additive is nevertheless to be considered as sucb only if — 
-doc generally recognized among exiwrts quallned by scientific training and 
experieoce to evaluate its toxicity or other imtentlaliry for harm, as having 
been adequately shown through scientific procedures or through prolonged use 
in food to be >.iIp for n«e wider the conditions of lis Intended oh*." 

AU tbe bills. Including those supported by Industry, contain a "generally 
recognized" clnuse in one form or another. It stems from tbe similar provisions 
•>f the rVderol Food, I'rug, and Osmetic Act wltb res|*ct to new drugs (sec. 
2111 <p) and |«i-«ileldc chemicals (sec. 409)). 

Tbe clause Is designed to exclude from tbe bills tbose substances wbicb accord- 
ing to tbe general consensus of competent scientific opinion are safe under tbe 
conditions of tbeir Intended use. While In all tbe ullls tbls exclusionary provi- 
sion is an integral tbougb negative part of tbe basic definition. It could wltb 
the same effect, and no less logic, have been placed In section 409 (a) — lu analog; 
to section +0S of tbe present act — which states under what circumstances a chem- 
ical additive shall be deemed to be unsafe, j" 
! hills, as drawn, the burden jvouiilhtj 



a.uu^wiFT^wiFWiiEr^iitww I'm; w i. t.'»i ■ .>.!■ 

134*1 Miraam»nuiI^oTrxratiorrn i,t.b\ '..•.<.■ ».iair>-i 



It I. Important ,„ note th.l nn.l.r 
jjjTgg lior.mm,.,! In nn enforce. 

r li.ttiit ggnrrallT rimfnltn) bi 



r 2 



lit concepToTTcrcnrinc consenaus is. to be sure, not susceptible of reduction 
to a mathematical formula, but It Is not obscure as a governing rule. Neither 
tbe Industry nor the Government baa encountered any material difficulty In 
determining under the present act whether new drags or jirstlctde chemicals 
are generally recognized hy appropriately qualified ei|*rt« as safe. 

At any rate— assuming that (in addition to tbe Secretary's exempting author- 
ity) some provision Is desirable for automatically excluding from the bill those 
additives which may safely be used wltboot submission for official safety cralna- 



(Ft* 



617 



63 



I JVL 'UBLie HtALTM MKVICS 



DEPARTMENT OF HEALTH It HUMAN SERVICES 

PUBLIC HtALTH ICHVICS 
•OOO AND OAUC ADMINISTRATION »MI LAOSLPHI A OlSTHiCT 



#00 US CvlUmWuH 
3n4 and CfMttngt luati 



July 16, 1992 Te>iO#>o«*- 31S.ftt?«3tb 

JUL 2 1992 



Dear Mr. 

Your letter written in response to the 

referenced Warning Latter has bean reviewed by the Agency. 

We note the corrective actions which has taken regarding the 
inconsistencies noted between the immediate bottle label 

and carton. However, as stated in our Warning Letter, we do not 
a gree that the pro duct is labeled In accordance with |411 of UlA 



aree that i^e product n inhaled in accordance with Mil cr U 
DfcC Act . inositol choline bltartrate. para-a^ncbantoic acid. 
citrus bioflavonoids and betalne hydrochloride are declared in 
milligram amounts or, the labe} , of this vitamin and mineral 
tablet. Such declarations give prominence to these ingredients 
which are not vitamins, minerals, or sources of vitamins and 
minerals in violation of 1411(b)(2)(B). 

Also, we are unable to concur with your proposal that this issue 
be deferred until NLEA regulations become final since f411 has 
been in effect sinoe 1976. 



Sincerely, 



Eugene C. Sohults 
Compliance Officer 
Philadelphia District 



ECS/bgp 



ATTAeHMttlr 
D 



64 



Mr. Towns. Mr. Silverglade. 



STATEMENT OF BRUCE SILVERGLADE, DIRECTOR, LEGAL 
AFFAIRS, CENTER FOR SCIENCE IN THE PUBLIC INTEREST 

Mr. Silverglade. Thank you. 

Good morning. I am from the Center of Science in the Public In- 
terest, and I would like to thank the subcommittee for the oppor- 
tunity to testify. 

CSPI believes a new era in nutrition has begun and that public 
health agencies should recognize that vitamins, minerals, and 
other components in food may be important for the prevention and 
treatment of chronic diseases. For example, there is certainly a 
rapidly growing body of scientific evidence that now supports the 
hypothesis that vitamins E and C may offer significant protection 
against heart disease and cancer. We believe that it is certainly 
time for the FDA to systematically examine this evidence and, if 
warranted, make it available to the public. 

However, as more and more consumers come to rely on this infor- 
mation and rely on dietary supplements to protect and promote 
their health, it is all the more important that health claims on sup- 
plement labels be reliable. 

The Congress took steps to ensure that health claims would be 
reliable when it passed the Nutrition Labeling and Education Act 
of 1990 and the Center for Science, as well as the American Heart 
Association, the American Cancer Society, and many other public 
health and consumer organizations worked very hard to ensure the 
passage of this legislation. Thus, we are very concerned about this 
topic. 

The food industry, we are happy to say, is complying with the 
NLEA, and misleading health claims on cereal boxes and other food 
labels have disappeared from the marketplace and consumers can 
now rely on health information found on food labels. The dietary 
supplement industry, however, lobbied Congress last year for a 1- 
year exemption from the NLEA and, as a result, misleading claims 
continue to plague the shelves of health food stores. 

Let me just show you what I mean. A fairly brand name cereal, 
Rice Crispies, used to be labeled as containing energy-releasing B 
vitamins. That is what the label used to say, and explained how 
B vitamins give you "energy." The claim was misleading, because 
while B vitamins help the body convert protein and fat and carbo- 
hydrate into energy in the sense that nutrition scientists would 
talk about that, they do not provide an added pick-me-up, as the 
label implied. 

That claim is no longer on the books and is not permitted on food 
labels at all, but it is still on the supplement labels. 

We were going to, I think, to show some slides, but we will just 
hold up some of these products instead. 

This is a product called B Total, which contains B vitamins, and 
the label says it helps convert food into energy. This was the type 
of claim taken off the Kellogg' s cereal label. These types of claims 
pervade the aisles of health food stores. These are not few isolated 
examples. They are made by the leaders in the industry. 

We have Mental Wisdom here; Memory Booster; Ocu Care for the 
eyes; Kidney Flush, if you have a problem with your kidneys; Brain 



65 

Pep, I suppose that is used if Mental Wisdom isn't good enough. 
These three products are interesting because they are all made by 
the same company and they all contain 100 percent wheat sprout 
concentrate but all carry different claims on the label. 

This is Cell Guard and so forth. This one is Ageless Beauty. The 
same company uses the same ingredients under a label of Exercise 
Edge. The same company uses the same ingredients under the 
label of Jet Stress, and so forth and so on. 

Here we have Ultra Male, Viril Actin, and Ultra Female, to be 
equal about it. These products here, the Ultra Male and Female 
and the Viril Actin, are made by a leading supplement, Nature's 
Plus. The chief executive officer of Nature's Plus is also director of 
the Nutritional Health Alliance, which has been generating quite 
a bit of the mail that your offices have been receiving on this issue. 
Materials distributed by the Nutritional Health Alliance state, 
"write Congress or kiss your vitamins good-bye." 

This is the sign. This is distributed to health food stores that be- 
long to the National Nutritional Foods Association, which will tes- 
tify in a little while, and it is posted in every health food store. 

My neighborhood health food store here in Washington has the 
sign up and there is also a model letter to send to your offices. Con- 
sumers are understandably panicked by these scare tactics and 
thousands of letters have been received by Congress. 

In our view, the industry is using scare tactics and playing a 
cruel hoax on the American public. The same members of the in- 
dustry that sell products that are supposed to improve sex drive 
and prevent hair loss, these products right here, are making delib- 
erate misrepresentations about FDA policy and the effect of the 
NLEA. You have heard FDA say they are not trying to take your 
vitamins away. 

Mr. Horn, Mr. Zeller, was a former staff assistant to the late 
chairman of this subcommittee, and so his veracity, in my mind, 
shouldn't be questioned. FDA is not trying to take vitamins away. 
What they are trying to do is crack down on these kinds of health 
claims, and these companies are generating mail to Congress be- 
cause they stand to lose hundreds of millions of dollars if these 
claims come off the label. Who would buy this product, Ultra Male, 
if it was accurately labeled as containing bull prostate glands? 

Thank you very much. 

Mr. Towns. Thank you very much, Mr. Silverglade. 

[The prepared statement of Mr. Silverglade follows:] 



66 



HEARINGS ON FDA' s REGULATION OF DIETARY SUPPLEMENTS 



STATEMENT OF 

Bruce Silverglade 
Director of Legal Affairs 

Center for Science in the Public Interest 



Before The 

Committee on Government Operations 

Subcommittee on Human Resources and Intergovernmental Relations 



* * * * 



July 20, 1993 
Washington, D.C. 



67 



Good morning. I would like to thank the subcommittee for 
the opportunity to testify. The Center for Science in the Public 
Interest (CSPI) is an independent, non-profit consumer 
organization. We were founded in 1971 and are now supported by 
more than 600,000 members and subscribers to Nutrition Action 
Health Letter. 

Today, I would like to discuss appropriate regulatory 
mechanisms for assuring that dietary supplements are safe and 
that the health benefits of these products are communicated 
properly to the public. 

CSPI's Position on Supplements 

But first, let me describe CSPI's position on supplements 
generally. We believe that a new era in nutrition has begun and 
that public health agencies should recognize that vitamins, 
minerals, and other components in food may be important for the 
prevention and treatment of chronic diseases. For example, it is 
time to acknowledge that a rapidly growing body of scientific 
evidence now supports the hypothesis that vitamins such as 
vitamin E and vitamin C, the provitamin beta-carotene, minerals 
such as zinc and selenium, and perhaps other substances in food 
that are not strictly essential in the diet, may offer 
significant protection against cancer, atherosclerosis, birth 
defects, cataracts, and other conditions. We believe that it is 
time to systematically examine and, if warranted, make this 
information available to the general public. 



68 



CSPI supports the right of consumers to purchase safe, 
quality manufactured, and appropriately labeled dietary 
supplements. We also recommend to consumers who want to hedge 
their bets to take certain supplements before definitive studies 
demonstrating the benefits of these products are completed. We 
certainly believe that consumers should have the right to 
purchase such products. 

Proper Framework for Communicating Health Benefits 

However, as more and more consumers come to rely on dietary 
supplements to protect and promote their health, it is all the 
more important that health claims on supplement labels be 
reliable. Congress, in the Nutrition Labeling and Education Act 
of 1990, (NLEA) set criteria for health claims that we believe 
are appropriate for both foods and dietary supplements. The food 
industry, we are happy to say, is complying with the NLEA and 
misleading health claims on cereal boxes and other food labels 
have disappeared from the marketplace. The dietary supplement 
industry, however, was granted a one year exemption from the NLEA 
last October and as a result, misleading claims continue to 
plague the shelves of health food stores. 

Let's look at some examples. This package of Kellogg' s Rice 
Crispies cereal used to be labeled as containing "Energy 
Releasing B-Vitamins. " The claim is misleading because while B- 
vitamins help the human body convert protein, fat and 
carbohydrate into "energy" as that term is used by nutrition 



69 



scientists, they do not provide an added "pick me up" as the 
label implies. Such claims are no longer permissible on food 
labels. 

Claims about B-vitamins and energy continue to appear on the 
labels of dietary supplement products, however, as shown by this 
label for Sublingual B TOTAL. 

Health food stores are loaded with supplements that make 
such claims. 

• Here, for example, we have a product called "Mental Wisdom," 
made by Enzymatic Therapy. 

• And here is a product called "Memory Booster" made by 
Nature's Bounty, Inc. 

• If that isn't enough, how about trying this product called 
"Brain Pep?" 

• Have a problem with your kidneys? Then try "Kidney Flush." 
I actually hope that if any members of the subcommittee did have 
a health problem involving kidney function that they would see a 
doctor before using a product such as this. 

• And here we have "Ocu Care" to ensure proper functioning of 
your eyes, and Slim Tea, an herbal product for dieting, and 
Nature's Plus "Viril Actin" for guess what? If you don't know, 
then try "Manhood Plus" made by N.I.S.M. , Inc. 

• Here are three different products made by Biotech Labs. One 
is called "Jet Stress," another is called "Exercise Edge," and a 
third is called "Cell Guard." They are all made from 100% wheat 
sprout concentrate. The same company also makes another product 



70 



called "Ageless Beauty," and another called "Runner's Edge," 

again all made from the same ingredient wheat sprout 

concentrate. 

• And here is my favorite, "Happy Camper" made by PEP 
Products, Inc., which promises that this "attitude food for the 
90's" will recapture the feelings of childhood. The NLEA would 
prohibit these types of health claims. 

The NLEA, however, also requires the Food and Drug 
Administration (FDA) to allow certain legitimate health claims. 
Prior to the enactment of the NLEA, all health claims on food and 
dietary supplement labels were considered by the FDA to be 
illegal, unapproved claims for so-called "new drugs." As a 
result of the passage of the NLEA, dietary supplement producers 
will, for the first time ever, be legally allowed to make well- 
founded health claims. 

This past January, the FDA issued final regulations allowing 
health claims stating that calcium supplements can reduce the 
risk of osteoporosis. The FDA announced last month that it will 
also allow health claims for folic acid and birth defects and is 
actively considering claims concerning the relationship between 
the consumption of anti-oxidants and chronic diseases. We 
believe the agency should consider allowing additional health 
claims for supplements. 

The NLEA sets up a procedure that permits consumers, 
supplement manufacturers, and others to petition the FDA to allow 
additional health claims. One need only show that the claim is 



71 



supported by "significant scientific agreement" — one does not 
have to provide the type of expensive clinical data necessary to 
gain FDA approval of a new prescription drug. This procedure 
ensures that health claims are reliable, protects consumers from 
fraudulent health claims, and increases the credibility of claims 
that are made. You can be assured that we will be working to see 
that the FDA faithfully implements this requirement. 

It's unfortunate that the supplement industry is campaigning 
for legislation that would repeal these provisions of the NLEA 
and open the flood gates to misleading health claims that will 
undermine the credibility of all supplement products. If the 
industry succeeds, it will become increasingly difficult for many 
consumers to distinguish between products that make well- 
supported health claims and others that claim a world of health 
benefits but deliver only broken promises. For example, how 
would the average consumer distinguish between a folic acid 
supplement that claimed to help reduce the risk of birth defects 
and a multi-vitamin supplement that claimed to boost the immune 
system and protect the body against HIV infection? The first 
claim is based on a significant agreement within the scientific 
community while the second is downright dishonest. If such 
legislation passes, consumers will increasingly become confused 
and disillusioned with all health claims for dietary supplements 
and that would be unfortunate because some supplements can play 
an extremely important role in protecting and promoting good 
health. 



72 



Tbe Industry has Misrepresented the Scope of the NLEA 

Major segments of the dietary supplement industry, including 
the Nutritional Health Alliance (NHA) , The National Nutritional 
Foods Association (NNFA) , Citizens for Health, the Life Extension 
Foundation, and others have charged erroneously that the NLEA 
allows the FDA to ban the sale of vitamin supplements. Other 
segments of the industry have claimed that FDA regulations 
implementing the NLEA will require consumers to obtain a 
prescription before purchasing a vitamin supplement. Neither of 
these charges are true. 

The NLEA only empowers the FDA to regulate claims on food 
and dietary supplement labels, not to ban or otherwise restrict 
the sale of safe products. FDA has announced its intention to 
use other authority granted to it by Congress in the Food, Drug 
and Cosmetic Act to assure that amino acids and herbal medicines 
are marketed safely. These actions, however, are not being 
proposed by FDA under the NLEA, but rather under the agency's 
authority to protect the public from unsafe food additives and 
drugs. 

Notwithstanding, some segments of the industry continue to 
make such charges as a basis for urging consumers to contact 
their elected representatives in Washington, D.C. in support of 
legislation that would exempt the industry from the NLEA. 

A cornerstone of the industry effort to win a permanent 
exemption from the NLEA is a grass roots letter writing campaign 
waged largely by health food store employees and customers who 



73 



are told that the FDA is trying to "take your vitamins away." 
Many Congressional offices have received reams of mail as a 
result of this effort. Here's why: 

• This leaflet distributed by the Nutritional Health Alliance, 
states "Company and store owners should explain to employees the 
importance of grassroots communications to Congress. Retailers 
must immediately begin asking customers to call Washington and 
tell Congress to keep supplements available." 

• This publication is another example of the type of 
literature distributed by the Nutritional Health Alliance. It 
states "Write Congress today or kiss your vitamins goodbye." 

• A letter sent to newspaper editors on behalf of the NHA 
states "you won't be able to buy Vitamin C over the counter in 
doses larger than 60 mg without a doctor's prescription." 

The FDA has stated on numerous occasions that it never had 
any intention of requiring prescriptions for safe supplements 
that contain more than 100% of the U.S. Recommended Daily 
Allowances for vitamins and minerals. However, the NHA, and its 
public relations firm, continue to make such charges. 

It should be noted that the director of the NHA, Gerald 
Kessler, is also Chief Executive Officer of Nature's Plus, which 
is a major manufacturer of dietary supplements. Nature's Plus' 
product line includes "Ultra Hair," a supplement powder 
advertised as containing essential nutrients needed to prevent 
hair loss, "Ultra Male," a dietary supplement made from raw 
bovine prostate concentrate and other bovine glands, and "Source 



74 



of Life," a multi-vitamin and mineral supplement that guarantees 
a "burst of energy" the very first time you use it. The products 
retail for approximately $13.00 to $20.00 for about a one month's 
supply. 

Nature's Plus was charged recently with violations of New 
York City's deceptive trade practices law for making misleading 
health claims for various products promoted as boosting the 
body's immune system. The Commissioner of the New York City 
Department of Consumer Affairs stated that by engaging in such 
practices, Nature's Plus was "preying on the fears" of people 
with AIDS. I have a copy of the notice of violation issued by 
New York City against Nature's Plus and I reguest that it be 
incorporated into the hearing record. 

The National Nutritional Foods Association also grossly 

exaggerates and misrepresents the FDA's regulatory authority 

under the NLEA. For example, in testimony before the House 

Appropriations Committee, NNFA refers repeatedly to proposed FDA 

regulations published in the Federal Register in November 1991. 

NNFA claims that the FDA's proposed rules would make it difficult 

to sell high potency vitamin and mineral supplements that contain 

greater amounts of a vitamin or mineral than is normally found in 

foods. NNFA claims that these proposed rules represent: 

"a back door attempt by the agency to undermine Section 
411 of the Food, Drug and Cosmetic Act which precludes 
limits on potency levels of dietary supplements." 1 

What the NNFA fails to mention is that whatever statements 

the FDA made in conjunction with its November 1991 proposed rules 

8 



75 



have been superceded by newer final regulations issued on January 

6, 1993. While the legal effect of the FDA's final rules on 

dietary supplements have been nullified by the moratorium 

established by the Dietary Supplement Act of 1992, 2 these 

regulations nonetheless represent the FDA's current policy. 

In its final regulations, the FDA makes clear that it will 

allow a health claim for a dietary supplement that contains more 

of a vitamin or mineral than is normally found in food. The 

preamble to the FDA's final rules states: 

"Nothing in the regulations would necessarily 
prevent a supplement from bearing a health 
claim when that supplement contains a level 
of a substance that exceeds the level 
achievable in the context of the daily 
diet." 3 

In accordance with this policy, the FDA has, in fact, 
allowed health claims for calcium supplements that contain more 
than 100% of the U.S. Recommended Daily Allowance for calcium. 4 

NNFA's repeated reference to the FDA proposed rules that 
have been superceded by final regulations is disingenuous, if not 
outright misleading. 

Other organizations, such as the Life Extension Foundation 
also use similar scare tactics to convince members of the public, 
who understandably may be wary of our current medical 
establishment, to write Congress in support of bills that have 
been drafted by lobbyists for the supplement industry and that 
will benefit the industry financially. A Foundation publication 
states, "We cannot guarantee that you will be able to buy 
vitamins very much longer." The Foundation has gone so far as to 

9 



76 



urge consumers to purchase a one year's supply of supplements. 
It should be noted that the Foundation operates a mail order 
pharmacy. 

In our view, these segments of the industry are playing a 
cruel hoax on the American public. The same members of the 
industry that sell products that are supposed to improve sex 
drive and prevent hair loss are making deliberate 
misrepresentations about FDA policy and the effect of the NLEA 
simply because they stand to lose hundreds of millions of dollars 
a year if they are forced to remove shaky and downright dishonest 
health claims from the labels of their products. Who, after all, 
would buy products like Ultra Male if they were labeled 
accurately as bull prostate? 

We wholeheartedly support the freedom to choose one's own 
form of health care, but that freedom isn't worth much unless one 
can make an informed choice, free of misleading claims that now 
plague the aisles of health food stores. 

Safety Regulation 

When consumers walk into a health food store, they have a 
right to expect that every product for sale there has been shown 
by the manufacturer to be safe. FDA presently has the authority 
to require supplement manufacturers to prove that their products 
are safe before they are placed on health food store shelves. 
This authority should be re-affirmed, and as I will explain, 
clarified, by Congress. 

10 



77 



The reason the FDA's authority needs to be clarified is that 
the Food, Drug, and Cosmetic Act does not contain a definition of 
a "dietary supplement." FDA is thus forced to call supplements 
either food additives or drugs in order to compel manufacturers 
to prove that a supplement product is safe. As a result, there 
has been uncertainty and controversy regarding the appropriate 
regulatory treatment of these products. CSPI supports 
legislation that would explicitly define the term "dietary 
supplement" and provide FDA with express authority to regulate 
such products. 

In much the same way that FDA regulates food additives, new 
dietary supplements could be deemed to be "safe" if they are 
"GRAS", i.e. generally recognized among experts as having been 
adequately shown through scientific procedures to be safe under 
intended conditions of use. Manufacturers should be required to 
notify FDA, however, when placing new supplements on the market 
that are deemed by the manufacturer to be "GRAS." This 
requirement would allow FDA to monitor dietary supplement 
ingredients that are being introduced into the market and to 
raise timely objections if there are concerns about an 
ingredient's safety. 

Supplements that are not "GRAS" would be sold only if 
manufacturers can demonstrate to FDA that there is a reasonable 
certainty that no harm will result from their intended use. 
Under such circumstances, FDA would issue a regulation 
prescribing the conditions under which a supplement may be safely 

11 



78 



used. 

Dietary supplement ingredients already on the market could 
be deemed "GRAS," provided manufacturers could adequately 
demonstrate through either scientific procedures or experience 
based on common usage, that ingredients are safe under the 
conditions of intended use. 

In light of the controversy that exists regarding the safety 
of some dietary supplements, including amino acids and herbs, FDA 
should be required to review the safety of all dietary supplement 
ingredients currently in use. Pending the results of this 
review, FDA should continue to allow ingredients to be marketed, 
unless the agency determines that a particular ingredient is not 
generally recognized as safe. 

In addition, dietary supplement manufacturers should be 
required to notify FDA if they acquire any knowledge that a 
supplement ingredient presents any potential health risk to 
consumers. Other federal consumer protection laws subject 
manufacturers of products — ranging from automobiles to 
televisions — to an affirmative reporting requirement and 
dietary supplements should be accorded similar treatment. 

To further ensure safety, supplements should be required to 
meet quality factor requirements (e.g., disintegration standards, 
potency standards) , that FDA would establish by regulation. 
Dietary supplement manufacturers should also be required to 
comply with regulations establishing good manufacturing practices 
and other quality control procedures that help keep sub-standard 

12 



79 



products off the market. 

To further protect consumers, supplement labels should 
include information disclosing any potential adverse effects from 
particular doses of the product. For example, iron tablets might 
be required to disclose the symptoms of iron overdose and its 
impact on children. Supplement labels should also include 
expiration dates, i.e. the date after which a product should no 
longer be consumed. Such requirements are appropriate given that 
more and more consumers are relying on supplements to protect and 
promote their health. 

Some segments of the dietary supplement industry believe 
that supplement safety should be regulated under less strict 
standards. For example, there have been suggestions that 
supplements be regulated in accordance with a standard similar to 
the "may render injurious" standard that FDA used to regulate 
added substances to food prior to 1958. Under this standard 
found in section 402(a)(1) of the Food, Drug, and Cosmetic Act, 
21 U.S.C. § 342(a)(1), the FDA must prove, by a preponderance of 
the evidence, that a food substance may be injurious to the 
health of consumers. 5 This standard has proved to be overly 
burdensome on FDA and ineffective at protecting the public's 
health. 

To remedy this problem, Congress passed the Food Additive 
Amendment of 1958 which shifted to manufacturers the burden of 
proving safety. 6 The Senate Report accompanying the legislation 
stated that under the "may render injurious" standard, the 

13 



80 



federal government was unable to prevent the use in foods of 
harmful substances. The report recognized that it took the FDA 
up to two years, and at times longer, to fulfill its statutory 
burden of proving that a substance was unsafe. Until such proof 
was forthcoming, food manufacturers were free to purvey to the 
consumer foodstuffs containing substances capable of producing 
illness, debility, or death. 7 

Regulatory frameworks that rely on such weak standards may 
prove equally ineffective at protecting the public from unsafe 
dietary supplements. Placing the burden of proof on the FDA 
enables potentially harmful supplements to remain on store 
shelves for years while FDA attempts to build a record, prepare 
its case, and carry its burden of proof. 

For example, Dr. Clayton's Herbs' "HERP-EASE" contains 
chaparral leaves as its primary ingredient. The ingestion of 
chaparral is attributed to cases of acute toxic hepatitis. 8 The 
FDA has issued a public warning concerning chaparral, and the 
industry has instituted a voluntary recall. If the FDA did not 
possess its current legal authority, it is unlikely that these 
steps would be taken. 

Another example of a potentially harmful dietary supplement 
is the amino acid, methionine. Methionine "has been implicated 
in precipitating episodes of hepatic encephalopathy." 9 The FDA 
recently announced that it plans to take regulatory action to 
bring amino acids into compliance with the Food, Drug, and 
Cosmetic Act. If FDA had to prove that supplements containing 

14 



81 



methionine may be injurious to health, products such as "Mental 
Wisdom" made by Enzymatic Therapy, Inc. and "Super Ripped" made 
by Nature's Best Food Supplements, could remain on store shelves 
for years before regulatory action, of the type recently 
announced by FDA, was taken. 

Regular consumption of large amounts of comfrey tea and 
comfrey pills can lead to severe liver damage. Comfrey contains 
alkaloids which are metabolized by the liver into toxic 
substances. These herbs are "prescribed" to treat abdominal 
pain, fatigue, and allergies. 10 Comfrey is banned in Canada, 
an action that FDA might not be able to take promptly in the 
United States if it lacked its current legal authority. 

The FDA must retain its authority to quickly remove other 
potentially harmful supplements from the marketplace. For 
example, supplement manufacturers produce and market ephedrine 
products for the treatment of bronchial asthma. These products, 
however, can be dangerous to asthmatics. Furthermore, ephedrine 
"stimulates the central nervous system and acts like amphetamines 
and caffeine." 11 Notwithstanding, products containing 
ephedrine, such as Traditional Medicinals, Inc. 's "Breath Easy," 
Nature's Way Products, Inc.'s "Breathe-Aid, " and Nature's Herbs' 
"Bronc-Ease, " are marketed as treatments for asthma. Ephedrine, 
listed as Ma huang, is also found in diet pills, such as Pep 
Products, Inc.'s "Diet Pep." 

Chamomile has been reported to induce systemic anaphylaxis. 
Additionally, "contact dermatitis due to chamomile is relatively 

15 



82 



common." 12 Products containing chamomile include herbal teas 
such as "Cold Care P.M." made by Traditional Medicinals, Inc. 

Willow bark contains a substance that metabolizes in the 
body like aspirin. Products containing willow bark should not be 
given to children who have the flu or chicken pox because they 
may develop Reye Syndrome. 13 A warning about the risks of Reye 
Syndrome is reguired on aspirin labels. FDA needs adeguate legal 
authority to promptly reguire similar warnings on the labels of 
willow bark supplements. 

Even vitamins, taken in large doses or by specific segments 
of the population, can be harmful. Iron supplements, taken by 
young children, can be fatal. According to the Centers for 
Disease Control and Prevention, iron poisoning is now the most 
common cause of child poisoning deaths in the United States. 14 

In light of this evidence, it is time to re-affirm and 
clarify FDA's authority to ensure supplement safety, not tie the 
agency's hands with an outmoded and inefficient regulatory 
standard that may endanger the public's health. 

Analysis of H.R. 1709 and Concluding Remarks 

While I recognize that this is an oversight hearing, I would 
like to state for the record that the consumer and public health 
communities oppose legislation introduced by Representative 
Richardson. 

More than 17 national public health and consumer 

16 



83 



organizations including the American Cancer Society, the American 
Association of Retired Persons, the American Heart Association, 
the Consumer Federation of America, Consumers Union, the National 
Consumers League, the Association of Schools of Public Health, 
the American College of Preventive Medicine, the Association of 
State and Territorial Health Officials, the Society for Nutrition 
Education, the American Dietetic Association, and numerous others 
have stated their objections to H.R. 1709, the so-called "Dietary 
Supplement Health and Education Act." I have letters from these 
organizations and I request that they be incorporated into the 
hearing record. 

In short, we are concerned that this legislation would 
provide consumers with less protection against unsafe dietary 
supplements and misleading labeling claims than is provided under 
current law. We are also concerned that the bill would make it 
more difficult for the FDA to take prompt enforcement actions 
against manufacturers of unsafe or improperly labeled products. 
In short, we have concluded that this legislation is not 
consistent with sound public health or consumer protection 
policy. 

I would like to thank the subcommittee for the opportunity 
to testify and I would be happy to answer any questions. 



17 



84 



Endnotes 

1. Statement of Richard Meyers, Legislative Director, National 
Nutritional Foods Association, before the Subcommittee on 
Agriculture, Rural Development, FDA and Related Agencies, April 

1. 1993, page 4. 

2. P.L. 102-571 

3. 58 Federal Register 2500 (Jan. 6, 1993) 

4. Ibid. 

5. united States v. An Article of Food , 678 F.2d 735, 741 (7th 
Cir. 1982) (citing United States v. Lexington Mill & Elevator 
Co. , 232 U.S. 399 (1914)); United States v. 2.116 Boxes of Boned 
Beef Weighing Approximately 154.121 Pounds , 516 F.Supp. 321 (D. 
Kan. 1981), aff 'd . 726 F.2d 1481 (10th Cir.), cert denied . 
Jarboe-Lackev Feedlots. Inc. v. United States . 469 U.S. 825, 
reh'g denied , 469 U.S. 1068 (1984). 

6. For a product already on the market, manufacturers need to 
demonstrate through either scientific procedures or experience 
based on common usage, that the ingredient is safe under the 
conditions of its intended use. 21 U.S.C. § 321(s) (1958). For 
a product not yet on the market, experts must generally recognize 
such product, as having adeguately shown through scientific 
procedures, to be safe under the condition of its intended use. 

7. See S. Rep. No. 2422, 85th Cong., 2nd Sess. (1958). 

8. See J. of Am. Med. Assoc, 269: 328 (January 20, 199 3); Katz, 
Miriam, M.D. and Fred Saibil, M.D., Herbal Hepatitis: Subacute 
Hepatic Necrosis Secondary to Chaparral Leaf . J. Clin. 
Gastroenterol, 12: 203-06 (1990). 

9. See Life Science Research Office, Fed'n of Am. Soc'y for 
Experimental Biology, Safety of Amino Acids Used as Dietary 
Supplements (1992) . 

10. See Bach, Nancy, et al., Comfrev Herb Tea-Induced Hepatic 
Veno-Occlusive Disease . Amer. J. of Medicine 87: 97-9 (1989). 

11. See Burros, Eating Well . N.Y. Times, July 14, 1993; Burros, 
Fating Well . N.Y. Times, June 16, 1993 at C8. 



18 



85 



12. See Ridker, Paul, Toxic Effects of Herbal Teas . Archives of 
Environmental Health, 42: 134 (1987). 

13. See N.Y. Times, June 16, 1993 at C8. 

14. See Iron Tablets Could Poison Children Fatally. CDC Says . 
Washington Post, February 19, 1993 at A13. 



19 



86 

Mr. Towns. Dr. Johnston. 

STATEMENT OF RICHARD JOHNSTON, MJD., SENIOR VICE 
PRESIDENT, PROGRAMS, AND MEDICAL DHIECTOR, MARCH 
OF DIMES BIRTH DEFECTS FOUNDATION 

Dr. Johnston. Thank you. Chairman Towns and members of the 
subcommittee, I am Richard Johnston, a pediatrician and senior 
vice president for programs and medical director of the March of 
Dimes Birth Defects Foundation. 

I want to thank you for this opportunity to testify and commend 
you for your interest in the role of government agencies in protect- 
ing the Nation's health. 

The March of Dimes' mission is to improve the health of babies 
through prevention of birth defects and infant mortality. Our work 
is consumer focused and community based using hundreds of thou- 
sands of volunteers serving through 115 chapters. Our foundation 
also invests in scientific research aimed at discovering new ways 
to prevent birth defects and infant mortality. 

I am here to discuss our interest in FDA's regulation of dietary 
supplements as it relates particularly to folic acid and the potential 
of folic acid to prevent birth defects. Neural tube defects consist 
primarily of anencephaly, absence of a fully developed brain, and 
spina bifida, abnormality of the spinal cord and the nerves that it 
carries. This group is one of the most common, severe birth defects 
that we have, estimated to occur as 2,500 births with neural tube 
defects in the United States per year. This is generally felt to be 
an underestimate because of underreporting. 

There have been 10 major scientific studies that have looked at 
the relationship between folic acid and neural tube defects, in par- 
ticular, whether folic acid in the diet might prevent neural tube de- 
fects. One study showed no effect. Of the 10, 9 showed a decrease 
in neural tube defects of 60 to 80 percent in the folic acid group. 

In one study, the positive effect of folic acid was so great that the 
study was stopped early because it was believed to be unethical to 
deny women in the control group this preventive intervention. The 
conservative estimate is that 50 percent of neural tube defects 
could be prevented if all women of childbearing age consumed at 
least 0.4 milligrams of folic acid daily. 

The results of these studies led to a recommendation by the U.S. 
Public Health Service in September of last year that all women of 
childbearing age should consume four-tenths of a milligram of folic 
acid a day to decrease the risk of having a pregnancy affected by 
a neural tube defect. 

The March of Dimes strongly supports this recommendation. 
This recommendation is targeted to all women of childbearing age 
because women often do not know that they are pregnant until sev- 
eral weeks after conception. And it is the first 2 to 4 weeks of preg- 
nancy that are critical to the formation of the brain and the spinal 
cord. Half of women who have a pregnancy have reported that it 
was not a planned pregnancy and it was not expected at the time 
that it occurred. 

The question, then, becomes how to achieve the preventive dose. 
Diet is generally deemed not to be practical. It is possible to get 
four-tenths of a milligram folic acid through diet, out not likely. 



87 

The easiest and the surest way is through taking a vitamin pill. 
Almost all multivitamins, those that you buy in the drugstore, gro- 
cery store, contain four-tenths of a milligram of folic acid, which is 
the recommended daily allowance for this water soluble vitamin. 

Supplementation, taking vitamin pills as a strategy, can be ex- 
pected to work most effectively for women who understand the 
need for taking multivitamins; who can afford to purchase them; 
who are concerned about the risk of neural tube defects; and who 
can remember to take the vitamin pill. Thus, women with edu- 
cation, means, and motivation will reduce their chances of deliver- 
ing a baby with a neural tube defect by an estimated 50 percent. 
However, this strategy is not expected to work well for women who 
are poor, with no resources to purchase vitamins, who live in medi- 
cally underserved areas where they do not receive advice on pre- 
ventive medicine, and who have limited education. 

Moreover, women of all types may find it difficult to sustain daily 
use of vitamin supplements over a period of 30 years. 

A third possibility, then, becomes to add folic acid to food prod- 
ucts. In November 1992, the folic acid subcommittee of FDA's food 
advisory committee recommended that FDA develop a fortification 
plan that would allow 90 percent of women of childbearing age to 
receive at least 0.4 milligrams of folic acid per day from all sources, 
but not allow other segments of the population, particularly older 
people, to receive high doses that could be harmful. 

Fortification of cereal grains would supply folic acid to women of 
childbearing age of all socioeconomic groups and would not require 
a change in eating habits. How might the FDA facilitate achieve- 
ment of a Public Health Service goal of having all women of child- 
bearing age in the United States receive the 0.4 milligrams of folic 
acid daily? The March of Dimes 

Mr. Towns. Doctor, can you summarize? The red light is on. 

Dr. Johnston. Oh. Let me conclude by saying that we have 
three specific recommendations. 

First, that the FDA authorize an appropriate health claim for 
folic acid. Second, that the FDA clarify the regulations regarding 
the 1 milligram threshold for folic acid. That level was determined 
years ago and did not include dietary folic acid. It was based on 
its application as a drug and did not consider total sources in the 
diet. And, finally, that cereal grain products should be fortified 
with a safe and effective level of folic acid. 

We encourage the process to move forward rapidly. We look for- 
ward to the release of the FDA's proposed rule and we look forward 
to the implementation soon of a strong public health tactic to re- 
duce the occurrence of these tragic birth defects. 

Mr. Towns. Thank you very much, Dr. Johnston. 

[The prepared statement of Dr. Johnston follows:] 



88 



March of Dimes 

Birth Defects Foundation 

National Government Affairs Office 
1901 L Street, N.W., Suite 260 
Washington, DC 20036 
Telephone 202 659 1800 
Fax 202 296 2964 




TESTIMONY OP 
THE MARCH OF DIMES BIRTH DEFECTS FOUNDATION 

BEFORE THE 

SUBCOMMITTEE ON HUMAN RESOURCES AND 

INTERGOVERNMENTAL RELATIONS 

OF THE 

COMMITTEE ON GOVERNMENT RELATIONS 

U.S. HOUSE OF REPRESENTATIVES 



PRESENTED BY 

Richard Johnston, M.D. 

Senior Vice President for Programs 

and Medical Director 



July 20, 1993 



89 



Chairman Towns and Members of the Subcommittee, I am Dr. 
Richard Johnston, Senior Vice President for Program and 
Medical Director for the March of Dimes Birth Defects 
Foundation. On behalf of the March of Dimes, I would like to 
thank you for this opportunity to testify today and commend 
you for your interest in the role of government agencies in 
protecting the nation's health. 

The March of Dimes mission is to improve the health of 
babies through prevention of birth defects and infant 
mortality. We carry out that mission through programs of 
health education, community services, research, and advocacy. 
Our work is consumer-focused and community-based, using 
hundreds of thousands of volunteers serving through 115 
chapters. Our Foundation also invests in scientific research 
aimed at discovery of new prevention approaches. 

I am here to discuss our interest in FDA's Regulation of 
Dietary Supplements as it relates to folic acid and the 
potential for birth defects prevention. In the interest of 
time, I will briefly summarize my testimony and submit the 
complete text for the record. 



1. THERE IS STRONG EVIDENCE IN FAVOR OF USING FOLIC ACID TO 
PREVENT NEORAL TUBE DEFECTS 

Neural Tube Defects are a Major Child Health Problem 

In the United States, there are approximately 60 million 
women of childbearing age (15 to 44 years), and each year 
there are 6 million pregnancies and 4 million births. 

Neural tube defects (NTDs) are birth defects occurring 
in the brain and spinal cord as they develop in a fetus. 
Each year in the United States approximately 2,500 babies are 
born with NTDs. They affect about one in every 1000 births, 
making these among the most common and severe birth defects. 
Anencephaly and spina bifida account for 90 percent of NTDs. 

o In the case of spina bifida (commonly called "open 
spine") a baby's spinal cord pushes out or never 
completely closes, resulting in brain damage and 
paralysis. Spina bifida is a leading cause of paralysis 
in the United States. 

o Babies with anencephaly are born with a severely 

underdeveloped brain, and virtually all die in the first 
days after birth. Over 500 babies die each year from 
this type of defect. 



90 



Like most birth defects, NTDs occur in families from 
every income, age, and racial/ethnic group (See Table 1 for 
rates by age and race of mother) . Women who have previously 
had one NTD-affected pregnancy are at much greater risk of 
having another and can be identified for preventive care. 
However, 95% of women delivering babies with NTDs have no 
prior history of such birth defects. 

The incidence of NTDs varies somewhat from area to area. 
Epidemics have been reported during the 1930s in 
Massachusetts and currently in China. Because there is no 
national birth defects surveillance system and most states do 
not have surveillance programs actively counting cases, we do 
not know the rate of NTDs for all areas of the country. 
However, clusters have been reported. For example, an 
cluster of anencephaly occurred in Brownsville, Texas between 
1989 and 1991, and a high incidence has been reported for the 
Central Valley of California. 

The Scientific Evidence is Strong 

During the past decade many studies confirmed a 
relationship between folic acid intake and birth defects. 
Published data are available from: randomized controlled 
trials, 1 ' 2 ' 3 non-randomized intervention trials, 4 ' 5 and 
observational/case-control studies. 6 ' 7,8,9 Only one of 
these studies found no protective effect. The level of 
protection found in the other studies ranged from 60% to 86% 
reduction in risk. 

In recent years, the quality of the evidence has 
improved with the results from two randomized, controlled 
trials. 3 

o In 1991, the British Medical Research Council reported 
that 4.0 mg of folic acid prevented the recurrence of 
NTD-affected pregnancies in 72% of women with a prior 
history of such defects. 2 

o In 1992, a study in Hungary found that 0.8 mg of folic 

acid supplements significantly reduced the risk of NTDs. 
The positive impact was so great that the study was 
stopped early on the grounds that control-group women 



a Randomized, controlled trials with humans are 
designed most like laboratory experimental studies and are 
believed to provide the best quality results. Individuals in 
the study are assigned to experimental and control groups in 
a random fashion and do not know to which group they are 
assigned. 



91 



ethically should not be denied this effective 
intervention . 3 

Half of NTDs Could be Prevented with Folic Acid 

Over the last 25 years, scientific evidence has been 
accumulating that consumption of folic acid, a B vitamin, can 
prevent some NTDs. Because neural tube development is 
complete by the 28th day of pregnancy, it is important that 
folic acid is taken in the weeks before conception and early 
in pregnancy (known as the "periconception period") . 

The U.S. Public Health Service estimates that at least 
50% of NTDs may be averted if all women of childbearing age 
consume folic acid daily at the 0.4 mg level. This 
translates into the prevention of birth defects among at 
least 1,250 infants each year through the implementation of a 
very simple nutrition/public health intervention. 

2. THE U.S. PUBLIC HEALTH SERVICE RECOMMENDS THAT WOMEN 
CONSUME FOLIC ACID TO PREVENT NTDS 

In November 1992, the U.S. Public Health Service 
recommended that all women of childbearing age in the United 
States consume 0.4 mg of folic acid daily to reduce their 
risk of having a pregnancy affected by NTDs. (See Attachment 
A) This recommendation is based on strong scientific 
evidence demonstrating that supplementary folic acid reduces 
the frequency of NTDs. The March of Dimes strongly supports 
this recommendation. 

The 0.4 mg of folic acid recommended by the Public 
Health Service to reduce NTDs is also the Recommended Dietary 
Allowance (RDA) . Every adult man and woman should consume 
this amount daily. However, consumption of folic acid has 
added protective benefits for women about to begin a 
pregnancy. 

The recommendation is targeted to all women of 
childbearing age who have not had a prior NTD-affected 
pregnancy because women often do not know they are pregnant 
until several weeks after conception — after the neural tube 
has developed and closed. Half of pregnant women report that 
the pregnancy was not planned or expected at the time it 
occurred. 

The March of Dimes Birth Defects Foundation views the 
release of the Public Health Service recommendation as an 
important opportunity to educate women about the prevention 
of NTDs through increased consumption of foods rich in folic 
acid and through vitamin supplements. The Foundation is 
developing and distributing new public and professional 



92 



health education materials, and March of Dimes chapters have 
initiated community-based projects to increase access to 
folic acid supplements among low-income women. 



3. IMPLEMENTATION OF THE PUBLIC HEALTH SERVICE 
RECOMMENDATION DEPENDS ON FDA ACTION 

Increasing Folic Acid Consumption through Diet 

Through careful selection of foods from the U.S. Dietary 
Guidelines and the Dietary Pyramid women can consume 0.4 mg 
of folate daily. However, implementation of this 
recommendation is difficult on standard American diets alone. 

o Folate b obtained from ordinary foods is not as well 
absorbed as folic acid from supplements or fortified 
foods. 

o In the United States, the average daily consumption of 
folate from diet is estimated to be only 0.2 mg. This 
means the average woman of childbearing age consumes 
only half of the RDA and thus half of the amount 
recommended to reduce her risk of having a baby with an 
NTD. 

At the same time, authorization of health claims for foods 
rich in folate might increase dietary awareness among women 
of childbearing age. 

Using Vitamin Supplements to Prevent NTDs 

Currently, the most direct strategy to implement the 
Public Health Service recommendation is for all women of 
childbearing age to take a vitamin pill containing 0.4 mg of 
folic acid. Consumption of sufficient folic acid through 
vitamin supplements is relatively easy because most 
multivitamin preparations available over-the-counter contain 
the recommended amount. 

Supplementation as a strategy can be expected to work 
most effectively for women who understand the need for taking 
multivitamins, who can afford to purchase them, who are 
concerned about the risk of NTDs, and who can remember to 
take the vitamin pill. Moreover, women who are consciously 
planning a pregnancy are more likely to be motivated to take 
folic acid supplements on a regular basis. However, as 
mentioned above, in this country one-half of all pregnancies 

b Folate is the term used for this vitamin as it is 
naturally found in foods. 



93 



are unplanned. Thus, women with education, means, and 
motivation will reduce their chances of having a baby with an 
NTD by an estimated 50%. 

However, not all women of childbearing age meet these 
criteria, and this strategy may largely exclude those who 
already face considerable health risks. This strategy is not 
expected to work best for women who are poor with no 
resources to purchase vitamins, who live in medically 
underserved areas with inadequate access to health services, 
and who have limited education. In fact, studies in Britain 
demonstrate that women in the two highest social classes are 
nearly twice as likely to take vitamins than women of lower 
social classes. 10 

In addition, evidence suggests that sustained use of 
supplements is difficult for many women. The case of calcium 
supplements for the prevention of osteoporosis further 
illustrates the limitations of supplementation alone as a 
strategy to reduce risk. Although there has been much public 
and professional education about the benefits for women of 
taking calcium supplements in adulthood, only 30% of women 
report taking calcium supplements. 11 

Food Fortification as a Strategy 

In November 1992, the Folic Acid Subcommittee of FDA's 
Food Advisory Committee recommended that FDA develop a 
fortification plan so that 90% of women of childbearing age 
could receive at least 0.4 mg of folate per day from all 
sources, while preventing excessively high folic acid intakes 
by non-target groups. 

Fortification of cereal-grain products combined with 
authorization of health claims on foods with substantial 
amounts of folic acid could be an effective approach for 
providing 0.4 mg of folic acid to the greatest number of 
women of childbearing age. This strategy does not require a 
change in eating habits that would be difficult to 
accomplish. 

FDA's research has shown that women of all socioeconomic 
groups across the country consume cereal-grain products. 
Fortification of cereal grains is the public health strategy 
used in the 1940 's when it was recognized that many people 
suffered from deficiencies of iron and certain B vitamins, 
due in part to the loss of these nutrients in the processing 
of whole grains. The Enrichment Act of 1942 encouraged 
fortification of refined cereal-grain products. 

o "Enriched" products are now fortified with approximately 
the same amount of thiamin, niacin, and iron and about 



94 



twice as much riboflavin as the original whole-grain 
product. 

o Folic acid fat any level) is not currently among the 
nutrients required for inclusion in these "enriched" 
products . 

o Enriched cereal-grain products include flours, breads, 
macaroni and pasta, corn grits, corn meals, farina, and 
rice. 

FDA currently is assessing whether an appropriate 
fortification level can be set. (See Attachment B for 
chronology of FDA action.) To be effective in preventing 
NTDs, a level of fortification must be set to ensure that the 
majority of women of childbearing age receive 0.4 mg of folic 
acid. At the same time, there is particular concern about 
the potential for complication and delay in diagnosing 
vitamin B12 deficiency (pernicious anemia) , primarily among 
eldery men and women, as an unintended consequence of 
increased folic acid intake. There is also some concern 
about the interference with chemotherapies, because some 
anti-cancer drugs are antifolates and therefore folic acid 
would antagonize these medications. Since patients on 
chemotherapy are under close medical supervision, it is 
possible to control their folic acid intake. 

4. MARCH OF DIMES VIEWS ON FDA ACTIONS ON FOLIC ACID 

The March of Dimes believes that FDA has an important 
role to play in protecting consumers from harmful products 
and false health claims. Given the potential for compounds 
to act as teratogens (i.e. to cause birth defects), 
assurances of food and drug safety are critical to our 
mission. 

At the same time, the March of Dimes seeks to have 
scientific evidence regarding new prevention strategies 
applied in the most effective manner. The weight of the 
evidence is clearly in favor of folic acid consumption to 
prevent NTDs. In this instance, the FDA and other agencies 
should act with due speed to implement the Public Health 
Service recommendation and to make folic acid widely 
available. 

Based on review of the chronology of events (Attachment 
B) related to FDA action regarding folic acid, the March of 
Dimes makes the following three recommendations for agency 
action: 

1. Authorize an appropriate health claim: We believe that 
the current FDA rules slow implementation of any 

6 



95 



strategy using vitamin supplements because of the limits 
on health claims for foods and dietary supplements 
containing folic acid. The evidence supports a public 
health recommendation and the policy should permit broad 
commercial and social marketing of products that could 
increase folic acid consumption. 

2. Clarify regulation regarding the 1 mg threshold: The 1 
mg maximum intake level is based on a standard set by 
FDA in 1971 for the threshold of folic acid dosages as 
drugs. This standard did not include the folate intake 
from diet and thus was not a threshold for total sources 
of folic acid. If the average dietary intake of folic 
acid of 0.2 mg is taken into account, the safety 
threshold for daily folic acid intake should be 1.2 mg 
total folic acid (from all sources including the regular 
diet, newly fortified foods, and supplements) . 

3. Fortify cereal grain products with a safe and effective 
level of folic acid: FDA's research has shown that 
women of all socioeconomic groups across the country 
consume cereal-grain products. Fortification of cereal 
grains would thus reach a broad population. In 
addition, it would be easy to implement because folates 
are inexpensive and can easily be incorporated into the 
current "enrichment" process used by many cereal-grain 
product manufacturers. 

We believe that a more thorough review of the evidence 
may support fortification with 350 meg of folic acid per 
100 grams of food — an amount adequate to assure that 
more than three-quarters of women would get 0.4 mg of 
folic acid. We share concerns that although women of 
childbearing age should receive an adequate amount of 
folic acid, persons at risk for B12 deficiency 
(pernicious anemia) should not consume an excess that 
would delay diagnosis of this condition. However, 
fortification with an inadequate amount of folic acid 
may be ineffective in preventing NTDs. 

Scientific evidence says we should move ahead with both 
health claims on folic acid and fortification of foods with 
an adequate amount of folic acid, while monitoring the impact 
carefully. 



96 



ATTACHMENT A 



U.S. PUBLIC HEALTH SERVICE RECOMMENDATION FOR THE 
USE OF FOLIC ACID TO REDUCE THE NUMBER OF CASES OF 
SPINA BIFIDA AND OTHER NEURAL TUBE DEFECTS 



"All women of childbearing age in the United States who are 
capable of becoming pregnant should consume 0.4 mg of folic 
acid per day for the purpose of reducing the risk of having a 
pregnancy affected with spina bifida or other NTDs. Because 
the effects of high intakes are not well known but include 
complicating the diagnosis of vitamin B12 deficiency, care 
should be taken to keep total folate consumption at 1 mg per 
day, except under the supervision of a physician. Women who 
have had a prior NTD-affected pregnancy are at high risk of 
having a subsequent affected pregnancy. When these women are 
planning to become pregnant, they should consult their 
physicians for advice." 



U.S. Department of Health and Human Services, Public Health 
Service, Morbidity and Mortality Weekly Report, September 11, 
1992, Vol. 41, No. RR-14 



97 



ATTACHMENT B 

CHRONOLOGY OF FDA ACTION ON FOLIC ACID 
Prepared by the March of Dimes Birth Defects Foundation 

• 1971 - FDA publishes conditions for use of folic acid as 
drug (36 FR 6843), setting the level at 1.0 mg. 



a 



1980 - FDA amends strengthens the precaution on labeling 
condition for folic acid (45 FR 69043) to emphasize that,, 
even at low levels, it may obscure pernicious anemia while 
neurological manifestations remain progressive. 

Currently, folic acid is approved (21 CFR 172.345) as a food 
additive provided that the "maximum intake of the food as 
may be consumed during a period of one day, or as directed 
for use in the case of a dietary supplement, will not result 
in daily ingestion of the additive in excess of 0.4 mg for 
foods labeled without reference to age or physiologic 
state." 

November 1990 - The Nutrition Labeling and Education Act of 
1990 (P.L. 101-535) requires the Secretary of Health and 
Human Services (and, by delegation, FDA) to issue regulation 
authorizing nutrient content and health claims on food 
labels. The amendments require that such regulations 
specifically address claims relating to 10 topics, including 
folic acid and neural tube defects (NTD) . 

March 28, 1991 - FDA publishes request for scientific data 
and information on 10 topic areas identified in the 1990 
amendments, including folic acid and NTDs. 

November 27, 1991 - FDA publishes proposed rule (55 FR 
60610) . The primary conclusion is that scientific agreement 
and the data are not sufficient to support the use of health 
claims related to folic acid and prevention of NTD. 

Early 1992 - CDC and FDA staff discuss potential 
inconsistencies between the FDA proposed rule and the CDC 
guidance (published July 1991) regarding use of folic acid 
for women at-risk of recurrent NTD. 

July 27, 1992 - CDC convenes meeting of 60 experts from 
inside and outside government to discuss "The Use of Folic 
Acid to Prevent Spina Bifida and other Neural Tube Defects." 

July-August 1992 - FDA, NIH and other Public Health Service 
(PHS) agency staff review CDC draft guidance recommending 
folic acid consumption by all women of childbearing age. The 
criteria for review were: l) consistency of association; 2) 
strength of association; 3) specificity of the association; 
4) degree of exposure; and 5) biological plausibility. 



98 



August 1992 - The March of Dimes submits comments to the FDA 
on their November 1991 proposed rule. Contrary to the 
report's conclusions, the March of Dimes supports the use of 
health claims and supplement labels which would advocate the 
use of folic acid and indicate its effectiveness in the 
prevention of neural tube defects. The March of Dimes' 
comments address the safety concerns presented in the 
proposed rule and conclude that the risk: benefit ratio 
supports a new, affirmative policy. 

September 1992 - The PHS publishes new recommendation for 
folic acid consumption of 0.4 mg per day by all women of 
childbearing age. (See Attachment A) 

November 1992 - First meeting of the FDA Food Advisory 
Committee. The committee serves as a technical and 
scientific body to advise FDA on issues of food safety, food 
science, and applied nutrition. 

November 1992 - FDA Folic Acid Subcommittee meets and 
invites 20 guest experts, as well as public comment. The 
members of this temporary subcommittee recommend that FDA 
develop a plan for food fortification such that majority of 
reproductive age women would get 0.4 mg per day. 
Subcommittee also votes against recommending that FDA allow 
health claim labeling on folic-acid containing foods. 

January 6, 1993 - FDA publishes a final rule (58 FR 2606) 
announcing its decision not to authorize a health claim for 
folic acid and neural tube defects, but states that it 
"plans to work expeditiously to authorize a claim, if 
appropriate." The rule cites the lack of a definitive 
appropriate level of folic acid consumption and safety 
concerns as key impediments to authorizing a health claim. 

The rule notes that advisors are focused on the following 
questions: "1) What is the target population for a folic 
acid-NTD health claim? 2) How does the information 
available on the effective level of intake affect options 
for implementation? 3) What safety concerns for the target 
population and for persons in the general population must be 
addressed? (4) If a claim is authorized, what is the most 
appropriate method for presenting it to the target 
population?" 

April 1993 - The FDA Folic Acid Subcommittee meets. 
Subcommittee members do not reach consensus of an 
appropriate level of food fortification. However, about 
half of the members now believe that the data support a 
health claim and that a label claim could assist in altering 
dietary patterns. 

June 16, 1993 - DHHS news release announces that, in July, 
FDA intends to issue new proposed rules on folic acid that 



99 



would authorize a health claim and amend the food additive 
regulation. 

June 30, 1993 - Symposium on "Folic Acid Prevention of 
Neural Tube Defects: Public Policy Issues" at the Teratology 
Society 33rd annual meeting. Presentations by Dr. Godfrey 
Oakley (CDC/NCEH) , Dr. Lynn Larsen (FDA), and Dr. Shirley 
Beresford (University of Washington) . 

July 17, 1993 - Proposed rule not yet published. 

September 1993 - Planned meeting of the FDA Food Advisory 
Committee and its Folic Acid Subcommittee to consider the 
proposed rule and related issues. 

December 1993 - Scheduled date for publication of final 
rule. 



100 



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101 



TABLE % Intervention studies of folic acid and neural tube defects (NTDs) 



Study 



Design 



Subjects 



Exposure 



Laurence, 
et a!. 
1931 11) 



UK MRC 
study, 
1991 (2) 



Randomized 
controlled 
trial in Wales 



Randomized 
controlled 
multicenter 
trial in UK 
and Hungary 



Smithells, Nonrandom- 
et al, ized controlled 

1983 [3) multicenter 
trial in UK 



Verge!, Nonrandom- 

et al, ized controlled 

1990 (4) trial in Cuba 



Pregnant women with prior 
NTO-affected pregnancy: 

Supplemented mothers 
tooic 4 mg of folic acid daily. 

Unsupplemented mothers 
took a placebo. 

Pregnant women with prior 
NTD-affected pregnancy: 

Supplemented mothers 
took 4 mg of folic acid daily. 

Unsupplemented mothers 
took a placebo. 

Pregnant women with prior 
NTO-affected pregnancy: 

Supplemented mothers 
took 36 mg of folic acid 
+ multivitamins daily. 

Unsupplemented mothers 
took nothing. 

Pregnant women with prior 
NTD-affected pregnancy: 

Supplemented mothers 
took 5 mg of folic acid daily. 

Unsupplemented mothers 
took nothing. 



Supplemented women 
were given 4 mg of folic 
acid or placebo daily at 
least 1 month before 
"conccTL'ion through 
the 1st trimester. 



Women given 4 mg of 
folic acid or placebo 
daily at least 1 month 
before conception 
through the 1st trimester. 



Women given 0.36 mg of 
folic acid + multivitamins 
or reported no use from 1 
month before conception 
through the 1st trimester. 



Women given 5 mg of 
folic acid or reported no 
use from 1 month before 
conception through 
the 1st trimester. 



2 NTD-pregnancies among 
60 supplemented women. 



4 NTD-pregnanciar-OTT.ong 
51 placebo-treated women. 

Relative risk = 0.40, not 
statistically significant. 

6 NTD-pregnancies among 
593 supplemented women. 



21 NTD-pregnancies among 
602 unsupplemented women. 

Relative risk = 0.28. p<0.05. 

3 NTD-pregnancies among 
454 supplemented women. 



24 NTD-pregnancies among 
519 unsupplemented women. 

Relative risk = 0.14, p<0.05. 



NTD-pregnancies among 
81 supplemented women. 



4 NTD-pregnancies among 
1 14 untreated women. 

Indeterminant protective effect, 
not statistically significant. 



60% reduction 
in risk. 



72% reduction 
In risk. 



86% reduction 
in risk. 



Complete 
protective 
effect. 



TABLE 2. Observational studies of folic acid and neural tube defects (NTDs) 



Study 



Design 



Subjects 



Exposure 



Results 



Mulinare, 
et al, 
1933 (5) 



Bower 

and Stanley, 

1939 (5) 



Case/control in 

metropolitan 

Atlanta 



Case/control in 
Western Australia 



Milunsky, 
et al, 

1989 (8) 



NTD case babies and 
normal control babies 

Pregnant women with- 
out a prior NTD-affected 
pregnancy. 



Spina bifida case babies 
and normal control babies. 

Pregnant women with- 
out a prior NTD-affected 
pregnancy. 



Mills, 


Case/control in 


NTO case babies and 


et al. 


California & 


normal control babies. 


1989 (7) 


Illinois 





Pregnant women with- 
out a prior NTO-affected 
pregnancy. 



Prospective cohort NTD case babies and 
in New England normal control babies. 



Pregnant women with- 
out a prior NTD-affected 
pregnancy. 



Multivitamin supplement 
containing 0—0.8 mg of 
folic acid at least 1 month 
before conception through 
the 1st trimester. 



Dietary folate and 
multivitamin supplement 
at least 1 month before 
conception through the 
1st trimester. 



Multivitamin + folate 
supplement containing 
up to 0.8 mg of folic acid 
+ diet at least 1 month 
before conception 
through the 1st trimester. 



Multivitamin + fola:e 
supplement containing 
0.1-1.0 mg of folic acid + 
diet at least 1 month before 
conception through 
the 1st trimester. 



24 supplemented & 
157 unsupplemented 
NTD case-women. 

405 supplemented & 
1,075 unsupplemented 
women controls. 
Odds ra;io = 0.40. p<0.05. 

77 NTD cases; 154 control 
mothers in study. The 
highest folate quartile 
was compared with the 
lowest. An increasing 
protective effect was 
observed from the lowest 
to the highest quartile. 
Odds ratio = 0.25, p<0.05. 

89 supplemented & 
214 unsupplemented 
NTO case-women. 

90 supplemented & 
196 unsupplemented 
women controls. 
Odds ratio = 0.91, not 
statistically significant. 

10 NTD-pregnancies 
among 10,713 women 
who took multivitamin 
+ folate. 

39 NTD-pregnancies among 
11,944 women who took 
multivitamins without folate. 
Relative risk = 0.28, p<0.05. 



60% reduction 
in risk. 



75% reduction 
in risk. 



No protective 
effect. 



72% reduction 
in risk. 



102 



REFERENCES 

1. Laurence KM, James N, Miller MH, Tennant GB, Campbell H. 
Double-blind randomized controlled trial of folate treatment 
before conception to prevent recurrence of neural-tube defects. 
BMJ 1981; 282:1509-11. 

2. MRC Vitamin Study Research Group, Prevention of neural tube 
defects: results of the Medical Research Council Vitamin Study. 
Lancet 1991; 338: 131-7. 

3. Czeizel AE, Dudas I. Prevention of the first occurrence of 
neural-tube defects by periconceptional vitamin supplementation. 
N Engl J Med 1992; 1992; 327: 1832-5. 

4. Smithells, RW, Nevin NC, Seller MJ, et al. Further experience 
of vitamin supplementation for prevention of neural tube defect 
recurrences. Lancet 1983; 1: 1027-31. 

5. Vergel RG, Sanchez LR, Heredero BL, Rodriguez PL, Martinez AJ. 
Primary prevention of neural tube defects with folic acid 
supplementation: Cuban experience. Prenatal Diagnosis 1990; 10: 
149-52. 

6. Mulinare J, Cordero JF, Erickson JD, Berry RJ. 
Periconceptional use of multivitamins and the occurrence of 
neural tube defects. JAMA 1988; 260: 3141-5. 

7. Mills JL, Rhoads GG, Simpson JL, et al. The absence of a 
relation between the periconceptual use of vitamins and neural- 
tube defects. N Engl J Med 1989; 321: 430-5. 

8. Bower C. Stanley FJ. Dietary folate as a risk factor for 
neural-tube defects: evidence from a case-control study in 
Western Australia. Med J Australia 1989; 150: 613-9. 

9. Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid 
supplementation in early pregnancy reduces the prevalence of 
neural tube defects. JAMA 1989; 262: 2847-52. 

10. S. Beresford. Presentation at a Symposium on "Folic Acid 
Prevention of Neural Tube Defects: Public Policy Issues" at the 
Teratology Society 33rd annual meeting. Tucson, Arizona, June 30, 
1993. 

11. Harris, Louis. Women's Health Survey . Commonwealth Fund, 
NY, 14 July 1993. 



103 

Mr. Towns. Ms. Stark. 

STATEMEMT OF SHIRLEY STARK, ASSISTANT ATTORNEY 

GENERAL OF NEW YORK 

Ms. Stark. Good morning. 

I would like to begin by thanking the chairman and the other 
members of the Government Operations Committee and the Sub- 
committee on Human Resources for this opportunity to discuss this 
very important issue. 

As you may note, the New York State attorney general, along 
with other State attorneys general, has been actively involved in 
the areas of food, drug, and dietary supplement advertising and la- 
beling over the past few years. In addition to filing comments with 
the FDA, we have taken enforcement action and we have entered 
into many settlement agreements with manufacturers and purvey- 
ors of these products regarding labeling and advertising issues. 

As you are well aware, there is a vigorous debate going on in 
Congress, in the media, FDA, and the public at large about now di- 
etary supplements should be regulated. Barely a week goes by 
without a report in one of the national newspapers documenting 
the dangers of some herbal product, a body building amino acid or 
some multivitamins. 

On the one side of the debate, the industry accuses FDA of trying 
to overregulate dietary supplements and to treat them as they 
would prescription drugs, thereby denying consumers ready access 
to supplements. On the other side of the debate are the consumer 
protection agencies who believe that supplements are not subject to 
nearly enough regulation and they cite examples of people dying or 
suffering severe injuries from the use of some dietary supplements. 

How is the debate going? Well, thus far, we think this public has 
been left in a fog and the debate has left Congress and FDA to 
grapple with the difficult issues of how to regulate these products. 

The use of some herbal supplements present a particularly dan- 
gerous situation, in our opinion. FDA has stated that many of the 
herbs currently marketed have no history of food use or use in con- 
centrated forms and are clearly hazardous. While marketers of 
these products sing their praises, they fail to reveal the potential 
dangers, thus fraudulently inducing people to consume these prod- 
ucts. 

In a recent article by Marian Burros in the New York Times, she 
focused on the dangers of herbal products such as comfrey, which 
has caused permanent liver damage, and chaparral, which can 
cause toxic hepatitis. Another New York Times Burros article de- 
tailed the frightening adverse reactions from consuming ephedra, a 
widely available herb marketed for everything from decongestion to 
weight loss. 

In the case referred to by Marian Burros, a Washington bank 
branch manager had not slept for more than 1 hour a night for 10 
nights and he began engaging in such irrational behavior after tak- 
ing ephedra for 6 weeks to lose weight that he was locked out of 
the office by the bank. As the bank manager, stricken with the 
ephedrine poisoning, later commented when he returned to normal, 
because ephedra was natural, he was seduced into the idea that it 
is safe. 



104 

Because no warnings are present on labels, consumers have no 
way of knowing potential dangers of such products or even that 
their reactions may be attributable to the herbs they ingested. 

Dietary supplements containing amino acids are another insid- 
ious example of supplements whose safety is suspect, yet which 
still are regulated as foods despite the fact they are touted as cures 
for all kinds of ailments. Even supplements which provide an ac- 
knowledged health benefit to certain segments of the population 
may contain hidden dangers which should be disclosed to the pub- 
lic. 

Public trust is high that the products designed to be consumed 
by the public are safe and are assumed to be tested by someone. 
Commonplace and seemingly innocuous vitamins and mineral sup- 
plements sometimes lack informative warning statements regard- 
ing the fact that they can be harmful in excessive amounts. 

Our office recently became aware of the problem of childhood 
poisonings caused by ingestion of adult formulations of iron, either 
alone or in combination with multivitamins. We learned that from 
1986 to the present, over 40 children under the age of 6 died as 
a result of eating iron supplements, thus making iron the No. 1 
killer of children due to poisoning. Yet the bottles containing these 
products do not carry any warning to parents to let 'em know 
that iron can be highly toxic or fatal to their children 

People treat these supplements as they would food, often leaving 
them uncapped and within easy reach of children, never dreaming 
any harm could result, yet because these products are marketed as 
foods, they don't carry warnings about the dangers of overdose. 
This must be changed and we are currently addressing the prob- 
lem. 

In the area of health claims for dietary supplements, we strongly 
believe supplements should be treated no differently from foods and 
should be subject to the same scientific standards of proof before 
being permitted to make a health claim. In our experience, manu- 
facturers will often latch onto the most preliminary scientific devel- 
opments and tout them as proven and conclusive facts to induce 
consumers to buy their products for their purported health bene- 
fits. These claims will then be passed onto supplement consumers 
as though they were scientifically substantiated truths. In other 
cases, manufacturers have stretched the conclusions of scientific 
studies to apply to their own products when that application is not 
justified. 

For example, in an enforcement action we brought against 
Stresstabs and One-A-Day vitamins, the manufacturers deceptively 
claimed that scientific studies proved their products could replace 
the vitamins and minerals lost through everyday stress. Their ad- 
vertisements led people to believe that ordinary stress of daily life 
results in the depletion of essential vitamins. In fact, there is no 
scientific basis for that kind of claim. 

One final thing. The National Association of Attorneys General, 
in a resolution passed at its summer meeting just a few weeks ago, 
called upon Congress to ensure that manufacturers of dietary sup- 
plements be held to the same standards as that required of other 
food and drug manufacturers whose products are subject to the ju- 



105 

risdiction of the FDA under the Food, Drug, and Cosmetic Act. 
FDA 

Mr. Towns. The entire statement will be included in the record. 

Ms. Stark. Let me state the resolution of these attorneys gen- 
erals is attached to my testimony. 

Thank you for the opportunity. 

Mr. Towns. Thank you very, very much. 

[The prepared statement of Ms. Stark follows:] 



106 



STATEMENT 

OF 

SHIRLEY STARK 

ASSISTANT ATTORNEY GENERAL OF NEW YORK 

btfore the 

HOUSE COMMITTEE ON GOVERNMENT OPEERATIONS 

SUBCOMMITTEE ON HUMAN RESOURCES AND 

INTERGOVERNMENTAL RELATIONS 

ON 
DIETARY SUPPLEMENTS 



107 



Good morning. I would like to begin by thanking Chairman Towns and the 
members of the Government Operations Sub-Committee for this opportunity to discuss the 
issue of regulation of dietary supplements. As you may know, the New York State 
Attorney General, along with other state attorneys general, has been actively involved in the 
areas of food, drug and dietary supplement advertising and labeling over the past few years. 
In addition to filing comments with the FDA, we have taken enforcement action and we 
have entered into many settlement agreements with manufacturers and purveyors of these 
products regarding labeling and advertisement issues. 

As you are well aware, there is a vigorous debate going on in Congress, in 
the media, at the FDA and among the public at large about how dietary supplements should 
be regulated. Barely a week goes by without a report in one of the national newspapers 
documenting the dangers of some herbal product, "body building" amino acid or even some 
multi-vitamins. On one side of the debate, the industry accuses FDA of trying to over- 
regulate dietary supplements and treat them as they would prescription drugs, thereby 
denying consumers ready access to supplements. On the other side of the debate are 
consumer protection agencies who believe that supplements are not subject to nearly enough 
regulation and cite examples of people dying or suffering severe injuries from the use of 
some dietary supplements. The debate has thus far left the public in a fog and Congress 
and FDA grappling with the difficult issues of how to regulate these products. 

While dietary supplements include seemingly safe products like essential 
minerals and vitamins which have recognized nutritional benefits, the term also encompasses 
many products which are of questionable safety, such as some herb products and high 
potency amino acid supplements. Nfany of these products have no recognized role in 
nutrition and make what appear to be therapeutic drug-like claims on their labels and in 
advertisements. Although the harm that can result from use of these products is as serious 
as that which can result from improper use of any prescription drug product, these 
supplements usually do not receive the same review as drugs. That fact became only too 
clear with the outbreak of illnesses in the summer and fall of 1989 during which 38 deaths 
resulted from the use of dietary supplements containing L-Tryptophan, an amino acid. 

Supplements which are marketed to be used as cures or treatments for disease 
are considered drugs and must be generally recognized by scientists as safe and effective 
for their intended use, or must have FDA approval prior to marketing. This requirement 
however, is most often honored in the breach. Consumers have suffered serious injury and 
death from unsafe and ineffective dietary supplements, which were neither generally 
recognized as safe and effective nor had received prior FDA approval, and yet were 
marketed to the public as cures for various diseases and ailments or as "magic pills" for 
weight loss. Other consumers have suffered serious injury and death as a result of 
delaying or foregoing proven treatments while they relied on false claims and promises of 
cures and pursued ineffective unconventional treatments with nutritional supplements. The 
dangers which can result from use of supplements effectively marketed as cure-alls are no 
less serious than those which can result from ingestion of a drug. 

The use of some herbal supplements presents a particularly dangerous 
situation. FDA has stated that many of the herbs currently marketed have no history of 
food use or use in concentrated forms, and are clearly hazardous. While marketers of 
these products sing their praises, they fail to reveal die potential dangers, thus fraudulently 



® 



108 



inducing people to consume these products. The herbal product, San-Kee, for example, was 
falsely marketed throughout the country as a Chinese herbal remedy for arthritis and has 
been shown to contain prescription drugs as well as unsafe levels of lead and cadmium. 
Most herbal products do not carry warnings on their labels and are not required to do so. 

An article by Marian Burros that appeared in The New York Times recently 
focused on the dangers of herbal products such as comfrey, which can cause permanent liver 
damage, and chaparral, which can cause toxic hepatitis. Another New York Times Burros 
article detailed the frightening adverse reactions that can result from consuming ephedra, 
a widely available herb marketed for everything from decongestion to weight loss. In the 
case referred to by Marian Burros, a Washington bank branch manager had not slept more 
than one hour a night for ten nights and began engaging in such irrational behavior after 
taking ephedra for six weeks to lose weight that he was locked out of his office. As the 
bank manager, stricken with ephedrine poisoning, later commented when he returned to 
normal, because ephedra was "natural" he was 'seduced into the idea that it's safe." 
Because no warnings are present on labels, consumers have no way of knowing the potential 
dangers of such products, or even that their reactions may be attributable to the herbs they 
ingested. 

A particularly glaring example of unsubstantiated therapeutic claims made for 
herbal supplements occurred a few years ago when the USHA Herbal Research Institute, 
run by a self-styled nutritionist calling himself "Dr. Sebi", advertised in the Village Voice 
and the Amsterdam News that "AIDs HAS BEEN CURED" by USHA and that they also 
specialize in cures for Leukemia, sickle cell anemia, herpes, lupus and other diseases. For 
an initial fee of $500 and $80 for each additional visit, patients were told they could be 
cured of AIDS and other diseases. The "cures" consisted of various herbal products, for 
each of which USHA made therapeutic claims. Eva Therapeutic Salve, for example, was 
referred to in USHA's brochure as follows: 

Eva Therapeutic Salve - "Eva is very effective on 
major skin problems, in prenatal use, against poor 
circulation, cancer, cysts, hemorrhoids and 
arthritis." 

In fact, these claims were false. Our office filed suit against USHA and 
entered a consent agreement under which USHA can no longer make therapeutic claims for 
any of its products. 

Dietary supplements containing amino acids are another insidious example of 
supplements whose safety is suspect, yet which are still regulated as foods, despite the fact 
that they are touted as cures for all kinds of ailments. FDA's Task Force Report on 
dietary supplements recommends that amino acids containing dietary supplements be treated 
as drugs because the primary intended use for these products is therapeutic and not 
nutritional. In this way, safety issues could be resolved by requiring that manufacturers 
prove product's safety before it could be sold. We believe that the implementation of such 
a policy by FDA would best protect public health and would help to prevent the onset of 
epidemics attributable to the use of supplements such as that which we witnessed with the 
amino acid L-Tryptophan. 



109 



Even supplements which provide an acknowledged health benefit to certain 
segments of the population may contain hidden dangers which should be disclosed to the 
public. Public trust is high that products designed to be consumed by the public are safe, 
and are assumed to be "tested" by someone. Commonplace and seemingly innocuous 
vitamin and mineral supplements sometimes lack informative warning statements regarding 
the feet that they can be harmful in excessive amounts. Our office recently became aware 
of the problem of childhood poisonings caused by ingestion of adult formulations of iron, 
either alone or in combination with multivitamins. We learned that, from 1986 to the 
present, over 40 children under the age of six died as a result of eating adult iron 
supplements - thus making iron the number one killer of children due to poisoning. Yet the 
botues containing these products do not carry any warning to parents to let them know that 
iron can be highly toxic or fatal to their children. People treat these vitamin/mineral 
supplements as they would food, often leaving them uncapped and within easy reach of 
children, never dreaming that any harm could result. Yet, because these products are 
marketed as foods, they do not carry warnings about the dangers of overdose. This must 
be changed and we are currently addressing this problem. 

In the area of health claims for dietary supplements, we strongly believe that 
supplements should be treated no differently from foods and should be subject to the same 
scientific standards of proof before being permitted to make a health claim. In our 
experience, manufacturers will often latch on to the most preliminary scientific 
developments and tout them as proven and conclusive facts to induce consumers to buy 
their products for their purported health benefits. These claims will then be passed on to 
supplement consumers as fit they were scientifically substantiated truths. In other cases, 
manufacturers have stretched the conclusions of scientific studies to apply to their own 
products when that application is not justified by the underlying science. For example, in 
enforcement actions we brought against Stresstabs and One-A-Day vitamins, the 
manufacturers deceptively claimed that scientific studies showed that their products could 
replace the vitamins and minerals lost through everyday stress. Their advertisements led 
people to believe that the ordinary stress of daily life results in the depletion of essential 
vitamins, and that these supplements could replace these lost vitamins. In feet, there is no 
scientific basis for a claim that emotional stress can deplete vitamins or that ordinary 
physical activity will result in such depletion. 

The fact that we had reached an agreement with Lederle to stop making such 
claims did not stop Miles from making similar types of claims for its One-A-Day vitamins 
several years later. Those ads claimed that "Daily stress can chip away at your B vitamins 
and rigorous physical training can lower your body's supply of essential minerals. That's 
why One-A-Day vitamins are uniquely formulated to put back what your world takes 
away." There is simply no support for the claims that ordinary types of emotional stress 
and routine exercise deplete the body's supply of vitamins and minerals. These ads were 
yet another example of advertisers preying on consumers' interest in products that 
guarantee improved health. Had the NLEA's scientific standard requiring significant 
agreement among experts regarding the validity of a health claim been in place and 
applicable, it is unlikely that such a claim would ever have been made. 

The National Association of Attorneys General, in a resolution passed at its 
summer meeting just a few weeks ago (a copy of which is attached), called upon Congress 
to insure that manufacturers of dietary supplements be held to the same standards as that 



110 



required of other food and drug manufacturers whose products are subject to the 
jurisdiction of the FDA under the Food Drug and Cosmetic Act. FDA must retain the 
audiority to prompdy remove potentially unsafe dietary supplements from the marketplace. 
Some of the legislation being proposed would make it more difficult for FDA to take action 
against dietary supplement products of questionable safety and efficacy. Any legislative 
proposal which shifts the burden to the underfunded and overworked FDA to prove that a 
supplement presents a substantial and unreasonable risk of illness or injury will result in 
consumers being subjected to unsafe products and unsubstantiated health claims for such 
products. The current law requires general recognition by experts of a product's safety and 
effectiveness or preapproval by the FDA prior to marketing a supplement for the cure and 
mitigation of serious disease. FDA's authority to stringently regulate such products should 
not be diminished. 

The Attorney General does not oppose the availability of dietary supplements. 
From an enforcement perspective, however, we have seen firsthand that claims made by 
dietary supplement manufacturers have often been among the most misleading and 
confusing claims in the food industry. Freedom of choice exists for consumers only when 
the products are safe, any claims of nutritional benefits are true, and the product is not 
being marketed for a serious therapeutic or disease-related purpose without prior FDA pre- 
market approval. Moreover, dietary supplements must be properly labeled and should 
accurately reflect what the product contains, directions for use and precautions necessary 
to assure safe use. Of course, any claims that appear on the label must do so in a truthful 
and nonmisleading manner. Finally, all disease related claims must meet FDA's standards 
for such claims and be limited to those claims pre-approved by FDA. 

Thank you once again for the opportunity to address the sub-committee on 
these important issues. 



Ill 



NATIONAL ASSOCIATION OF ATTORNEYS GENERAL 

Adopted 

Sumner Meeting 
July 7-10, 1993 
Chicago, Illinois 

RESOLUTION 

DECEPTIVE CLAIMS IN DIETARY SUPPLEMENT 
LABELING AND ADVERTISING 

WHEREAS, the federal Food, Drug and Cosmetic Act prohibits the use of deceptive 
cJaims on the libeling of foods (including dietary supplements), drugs and cosmetics; and 

WHEREAS, the federal Food, Drug and Cosmetic Act was recently amended by the 
Nutrition Labeling and Education Act of 1990 ("NLEA"), to allow only health claims which are 
properly supported by scientific evidence to be made for foods; and 

WHEREAS, one of the goals of Congress in adopting the NLEA was to make nutrition 
labeling uniform and non-deceptive so that American consumers could compare products; and 

WHEREAS, one of the goals of Congress in adopting the NLEA was to prevent 
members of the oublic who are trying to follow me advice of medical and public health officials 
from being confused by inaccurate, misleading and incomplete labeling; and 

WHEREAS, the Attorneys General have been interested in the area of nutrition labeling 
and deceptive labeling and advertising problems for mmy years (see Resolution VI, adopted 
National Association of Attorneys General Summer Meeting, 1988); and 

WHEREAS, the Attorneys General of many of the states filed comments wim the Food 
and Drug Adiruntstration (FDA) regarding the FDA's proposed regulations to implement the 
provisions of NLEA, wherein they stressed the need for the regulations to foster NLEA's goal 
of preventing deception in the labeling and advertising of foods; and 

WHEREAS, the Attorneys General are concerned about the spread of health fraud and 
the millions of dollars spent annually by the American public on supposed health care products 
which are fraudulently labeled and advertised; and 

WHEREAS, the consequence of inadequate regulation of products which improperly 
. claim to have a beneficial effect on the public's health is that the American public, at worst, is 
induced to use products which may in fact be harmful to their health, and at best, is fraudulently 
induced to spend millions of dollars annually on worthless or inconsequential products; and 

WHEREAS, the Attorneys General, because of the legal duty to halt deception and 
fraudulent claims made for products wWrin the purriew of me federal Food, Drug aiidCtoanetic 
™L.°* **££' and thetr state laws spend their resources fighting health fraud schemes and 
products which cost the citizens of then- states millions of dollars a year; and 



112 



WHEREAS, many of the mote outrageous claims made are made by the prooucers or 
products classified as dietary supplements ana in the past many of these producers have made 
fraudulent claims for their products which claims are currently illegal and cannot be made for 
food products; and 

WHEREAS* there are currently various proposals being discussed in Congress which 
would in the future exempt dietary supplements from having to continue tc Comply w-ch the 
same requirements as food or over-the-counter drug products when makv^eiaims about a 
product's benefits and effects; would exempt dietary supplements from havirt&Hs comply with 
the requirements of the NLEA which prohibits the use of misleading, urj«ostantiaieA\ and 
deceptive health claims about products; would remove the Food and Dryo Administration's 
authority to protect consumers from potentially unsafe dietary supplements: arU would seriously 
curtail the FDA's authority to take action against manufacturers who make raise and deceptive 
claims about their dietary supplement products', and 

WHEREAS, the Attorneys General believe that manufacturers of dietary supplements 
should be subject to the jurisdiction of the Food and Drug Administration and that in making 
claims about their products they should be held to the same standard as that required of other 
manufacturers whose products are subject to the jurisdiction of the Food and Drug 
Administration under the federal Food, Drug and Cosmetic Act and the NLEA: that health 
claims for dietary supplements must be supported by at least the same scientific, standard as 
required for health claims for other products under the NLEA; and that FDA must retain 
adequate authority to be able to promptly remove potentially unsafe dietary supplements from 
the marketplace; 

NOW, THEREFORE, BE ITRESOLVEDTHATTHENATIQNAL ASSOCIATION 
OF ATTORNEYS GENERAL: 

1. calk upon Congress to insure: that manufacturer? of dietary supplements remain 
subject to the jurisdiction of the Food and Drug Administration; that they be held to the same 
standard as that required of other manufacturers whose products are subject to the jurisdiction 
of Food and Drug Administration under the federal Food, Drug and Cosmetic Act and the 
NLEA; that health claims for dietary supplements must be supported by at least the same 
scientific standard as required for health claims for other products under the NLEA before they 
can be made: and that FDA retain adequate authority to be able to promptly remove potentially 
unsafe or deceptively labeled dietary supplements from the marketplace; and 

2. authorizes its Executive Director and General Counsel to make these views known 
to members of the Administration, the Congress and other interested parties. 

93*mr*i.u3 



113 

Mr. Towns. Let me thank all of you for your testimony. 

Let me begin, I guess, with you, Ms. Stark, and, I guess, Mr. 
Silverglade. Exactly how prevalent are these fraudulent claims on 
dietary supplements? Are we talking about a bad apple here, a bad 
apple there, or are we talking about a whole bushel? 

Mr. Silverglade. It is more like the whole bushel. When we 
first worked to get Congress to pass the NLEA, we were focusing 
primarily on food products, and the misleading health claims on di- 
etary supplements really make the misleading claims that the food 
industry once made really pale in comparison. These claims are 
outright fraud, many of them. 

I know in my health food store in my neighborhood, I would say 
20 to 30 percent of the products are of this type. So we are not 
talking about a few rotten apples. These claims are made by the 
leaders of the industry, and as I have said, the same leaders of the 
industry are organizing the letter writing drive to Congress. 

Ms. Stark. I would agree with, Mr. Silverglade. I took the shut- 
tle down here this morning, and if you took a look at some of the 
health magazines, you would see they are full of advertisements 
which deceptively tout the benefits of taking certain products, and 
they are really making health claims for these products which can- 
not be substantiated. 

Mr. McNamara. Mr. Chairman, will you permit a response from 
a different perspective? 

Mr. Towns. In this instance, I want to follow this train of 
thought and then we will come back and you will certainly be al- 
lowed to provide a different perspective. 

Exactly how many enforcement actions has the State of New 
York brought against dietary supplements in the past 5 years? 

Ms. Stark. We have focused on the issue of fraudulent and de- 
ceptive claims for foods primarily, although we have certainly gone 
ahead and brought some actions against deceptive health fraud 
claims for supplements as well. 

We have worked in conjunction with other States across the 
country on some of their actions against fraud and deceptive adver- 
tising of supplements. I can't give you a number. I am not the only 
person in the office who is working on deceptive claims by supple- 
ments, however, there have certainly been a number of actions. 

Mr. Towns. Mr. McNamara, you can respond. 

Mr. McNamara. Mr. Chairman, I would like to be clear that, 
first, so far as I know, no one in the dietary supplement industry, 
and certainly insofar as I speak for a client here — I am talking 
about Utah Natural Products Alliance — no one there is encouraging 
this committee or any government agency to endorse or tolerate 
fraud in the marketplace. The question really comes down to what 
kind of remedy is the appropriate means for responding to claims 
that anyone decides are inappropriate by whatever the national 
standard should be. 

Now, Mr. Silverglade said that these represent, in his judgment, 
and for hypothetical purposes let's say he is right, 25 to 30 percent 
of a health food store. If the other two-thirds to three-quarters are 
not making claims of this sort, then let us talk about the remedy 
that the government is trying to put in place and think about how 
it would apply here. 



114 

What the government has proposed is that a company may make 
no representation of any kind that links a nutrient, any nutrient, 
to any disease or to any health-related condition at all, unless that 
representation has first been approved by a regulation to be issued 
by the FDA; a process that typically takes 2 to 5 years, is very ex- 
pensive, and requires an in-place government bureaucracy to keep 
regulations up-to-date, to hear the petitions, and to modify the reg- 
ulations as changes need to be made. 

In essence, what the FDA is proposing is a system of 
preclearance, a prior restraint on free speech. In the alternative, 
what we have in place already, but apparently not in these, my col- 
leagues' minds, sufficiently enforced, is a law that already makes 
it illegal. It is a criminal offense in this country to sell a dietary' 
supplement product with a label that is false or misleading in any 
particular. 

FDA's existing remedies under the law include civil seizure ac- 
tions, injunction actions, criminal prosecutions, requests for recall. 
The U.S. Supreme Court, in a major U.S. precedent, has upheld 
FDA's ability to take even criminal action against people who make 
unauthorized disease claims for dietary supplement products. 

Now, what, at most, I am hearing here is an allegation that the 
FDA has not dealt with an issue under existing Taw, and that, 
therefore, they should be given more power. It would seem to me 
that instead trie oversight committee should be saying to FDA, why 
have you not been out taking action under existing law against 
products that you regard as inappropriate? 

Because the consequence here is — the consequence is the honest 
purveyors, the people who have products about which they wish to 
make truthful and nonmisleading statements, will not be allowed 
to go into the marketplace with their truthful and nonmisleading 
statements until those statements have cleared the FDA bureauc- 
racy in a rulemaking proceeding — a delay of 2 to 6 years. 

Mr. Towns. Mr. Silverglade, if you wish to respond, and then I 
would yield. 

Mr. Silverglade. Just 30 seconds. There is a 120-day time limit 
in the Nutrition Labeling and Education Act for the FDA to re- 
spond to petitions for health claims. The products here are on the 
market because the old law didn't work. That is why Congress 
passed the Nutrition Labeling and Education Act. 

The FDA would literally need an army of lawyers to bring indi- 
vidual case-by-case enforcement actions against these dozen or so 
products, but then there are another couple of hundred in my 
health food store, and then they would have to go to the health 
food store in California and bring another couple hundred cases. It 
is impossible. 

That is why Congress passed the 1990 law, which sets up an effi- 
cient regulatory enforcement mechanism to get misleading claims 
off the market once and for all, and that is why the dietary supple- 
ment industry is so scared of the NLEA and is pushing to get an 
exemption from it. 

Mr. Towns. All right. 

Mr. McNamara. The law does not require that FDA complete its 
rulemaking in 90 days. The law merely requires they make up 
their mind about whether to proceed. There is absolutely no dead- 



115 

line in the NLEA or in FDA's regulations for the agency to com- 
plete its rulemaking proceeding on any health-related statement. 

Mr. Towns. OK. Let me yield to Congressman Schiff. 

Mr. Schiff. Thank you, Mr. Chairman. Because of the number 
of witnesses and the number of members here showing interest in 
this issue, I will be brief. And I hope by generalizing I don't leave 
out anything important, but I have heard kind of different mes- 
sages from each of the panelists and I want to make sure I have 
the message correctly and maybe ask one question. 

Mr. McNamara, I hear your message is the FDA is off the wall. 
Is that a pretty — at least in some of the things they have done with 
respect to addressing dietary supplements and how they have ap- 
proached it — is that a fair conclusion or not a fair conclusion? 

Mr. McNamara. We believe, Mr. Schiff, that, with respect to die- 
tary supplements, FDA has been unreasonably aggressive in inter- 
preting and enforcing the existing law, both with respect to safety- 
related issues and also with respect to labeling. On top of that, if 
you get a warning letter from the FDA that tells you that your 
company is in violation of the law, FDA will deny you the right to 
get judicial review of that letter. 

That is the third point you gentlemen need to stop and consider 
in terms of review and oversight of FDA. FDA now issues these 
devastating warning letters to companies, telling them that their 
products are in violation — for example, they are selling an unap- 
proved food additive, like black currant oil, and then 

Mr. Schiff. I have to interrupt at this point. 

Mr. McNamara. You cannot even get judicial review. I believe 
that is an abusive system. 

Mr. Schiff. I hear your message, Mr. Silverglade, as the cre- 
scendo of questioning of the FDA's regulation of dietary supple- 
ments is in fact a facade from certain manufacturers that don't 
want their labels and claims questioned; is that a fair summary? 

Mr. Silverglade. That is a fair summary. 

Mr. Schiff. In your view, as a generality, do you believe that di- 
etary supplements should be, and I will go to Ms. Stark on this 
one, too, who has a similar point of view, I think, do you believe 
that on the basis of potency, or some other test, any existing die- 
tary supplement should be classified as a drug for the purpose of, 
by implication, requiring a medical prescription for their use? 

Mr. Silverglade. I don't have the information to answer that 
question. In general, no, we don't believe that to be the case. FDA 
is looking at amino acids and so forth. 

The problem with calling dietary supplements a drug or a food 
additive, and I think that is the problem, is that FDA has no 
straightforward authority for regulating the safety of dietary sup- 
plements. Congress never gave the FDA direct, express authority 
to regulate something called "a dietary supplement." 

Mr. Schiff. You don't think it is implicit in the regulation of 
other 

Mr. Silverglade. It is either regulated as foods or food additives 
or drugs. The reason FDA has gone to court and looked at the 
judge and said, this dietary supplement is a food additive is be- 
cause that is one of the few legal provisions the agency has to de- 



116 

mand that the manufacturer prove in advance that the product is 
safe. 

We think when consumers walk into health food stores, that they 
already believe the manufacturer has shown every product in that 
store for sale to be safe. Who would not think that was the case? 
But that is not the case because FDA doesn't have the authority 
to directly tell dietary supplement manufacturers to prove that 
their products are safe before putting them on the market. The 
only way to do it is to say this is a food additive or a drug, and 
that is where the confusion starts. 

Mr. Schiff. Ms. Stark, are there any items you would rec- 
ommend on your list of reforms be regulated as a drug requiring 
a prescription for dispensation? 

Ms. Stark. Our position, and I believe the law requires, that if 
a product makes a therapeutic claim that it can — not a nutritional 
claim but a therapeutic claim, that product is to be treated as a 
drug. Just because it is a high dosage or high potency vitamin, does 
that make it into a drug? Absolutely not. 

I agree with the FDA's determination to open the floor to com- 
ments about the safety of those kinds of products, but I am cer- 
tainly, the attorney general's office is certainly open-minded on 
that issue. 

Mr. Schiff. Dr. Johnston — by the way, I apologize to the wit- 
nesses. I have cut them off a little only because of the number of 
questions coming. 

Dr. Johnston, if I hear you, at least the message you have 
brought to this hearing, is the desire that the FDA permit and pos- 
sibly encourage the use of formic acid. 

Dr. Johnston. Folic acid. 

Mr. Schiff. Right. Formic acid comes from insects, doesn't it? 
Sorry about that. 

Dr. Johnston. Yes. 

Mr. Schiff. Folic acid. Is it not now allowed to be used? I am 
not sure I understand the status now. 

Dr. Johnston. Yes, we are not asking that this law be changed. 
It is allowed to be used. However, you cannot put on your product 
a statement that the product, for example bread or cereal, contains 
folic acid which can reduce the likelihood of neural tube defects. 

Mr. Schiff. But is folic acid, can it be sold now? 

Dr. Johnston. It can be sold. It is sold. It is already in some ce- 
reals. There is no health claim made. We feel the health claim 
would allow the commercial sector and also foundations like us to 
get across the message that it does reduce birth defects. 

Mr. Schiff. So you want the FDA to approve this particular 
health message? 

Dr. Johnston. A health claim in this particular instance within 
the bounds that need to be set carefully by the FDA. 

Mr. Schiff. I want to thank the witnesses. 

Thank you, Mr. Chairman. 

Mr. Towns. Thank you very much, Congressman Schiff. I yield 
to Congressman Sanders. 

Mr. Sanders. Thank you, Mr. Chairman. 

I am in a bit of a quandary, so maybe you can help me out, and 
this is the dilemma that I have. For Mr. McNamara, if the law cur- 



117 

rently is strong enough, and if in fact Mr. Silverglade is correct and 
some of those products are absolute frauds, why are those products 
on the market today? Briefly. 

Mr. McNamara. Because the FDA has not, assuming his charac- 
terization of them is correct, hypothetically, because the FDA has 
not exercised the existing authority which it has in abundance. 

Mr. Sanders. You think they have the authority to deal with 
that. 

Mr. Silverglade, do they have the authority to 

Mr. Silverglade. This is a cat and mouse game, because some 
members of the subcommittee believe the FDA is putting too much 
resources, too many workyears into regulating the supplement in- 
dustry. 

To use the old law before the NLEA, the FDA would have to put 
in even more workyears. They would have to hire dozens more law- 
yers to bring individual case-by-case enforcement actions. 

Mr. Sanders. OK Let me ask you and Ms. Stark a question on 
the other side. 

Some people are not convinced that the U.S. Government or, in 
fact, established science knows the answers to many of the serious 
health problems facing modern society. For example, the whole 
area of cancer prevention. A terrible debate is going on. And it has 
not been orthodox science of the United States that has been lead- 
ing the effort, for example, in terms of cancer prevention. 

When we talk about nutrition, that didn't come from the govern- 
ment. Yet people who they thought were wackos 20 or 30 years ago 
were talking about these ideas and they gradually filtered up. 

Is there not a concern on your part that this overregulation may 
in fact slow down progress in terms of finding alternative ap- 
proaches to disease, and then, in fact, shouldn't Americans, who 
presumably control their own body, be able to have more options 
than the FDA might allow? 

That is my concern with your position. Can you respond to that? 

Ms. Stark. We don't want to take away options from the Amer- 
ican public, and I think I made that clear in my testimony. What 
we are worried about is the prevalence of deceptive claims out 
there. And what happens is, you know, an advertiser, in a very ef- 
fective way, will latch onto a very preliminary report in the New 
England Journal of Medicine and say this is now a proven fact, 
even though the article itself may talk about the fact that addi- 
tional studies need to be conducted in order to make this a proven 
fact. Nevertheless, the advertiser doesn't inform the public of that 
in the 30 second spot it shows on TV. 

Mr. Sanders. I would suggest that most of the promises made 
by products which are advertised on TV are lies. 

Mr. Silverglade. That is fairly true, most of the products are 
deceptively advertised. 

Mr. Sanders. Why are you so specifically concerned about these 
products? 

Mr. Silverglade. These products involve health, and it is very 
important that the Federal Government establish a mechanism for 
the dissemination of consistent health information. If we allow lots 
of preliminary evidence about the potential benefits of some of 
these products to be put on labels, if that is the Federal Govern- 



118 

merit's public health policy and the evidence doesn't pan out, as 
much of it may not pan out, then consumers will throw their hands 
up in the air and say, we don't know what to believe, and that 
would be a great tragedy, because CSPI is one of the first organiza- 
tions to recognize supplements can be beneficial to health. 

We were the wackos back in the early 1970's that said people 
should eat whole wheat bread and eat more foods higher in fiber 
before the health committees in the House and Senate and we were 
accused of being the wackos, so I am sensitive to your concern. 

But our concern is if we don't have an efficient enforcement 
mechanism to separate fact from fiction, consumers won't know 
what to believe. Folic acid can reduce birth defects but a product 
labeled as protecting your immune system and protecting you from 
AIDS is not truthful. How would the average consumer know the 
difference unless somebody in the government is sifting through 
these claims and saying some claims are well supported and others 
are not? 

Ms. Stark. I think that people believe there is someone out there 
watching out for their health, and when the product makes a 
health claim, that there is someone reviewing that health claim to 
make sure it is a truthful health claim. Unfortunately, there are 
many claims out there that are deceptive. 

Mr. Sanders. Well, as someone who has dealt with some of these 
issues, if anyone thinks the government is out there looking after 
their health, they are certainly being deceived, and maybe we 
should deal with the regulation on that one. But thank you. 

Mr. McNamara. Mr. Sanders, I can give you an example of an 
FDA action you might want to look at in this context because it is 
attached to our statement. There is a one-page FDA letter that you 
may want to ask why they are taking action against? 

We have a letter FDA wrote to a dietary supplement company 
saying it was misleading for the company simply to tell how much 
of the various ingredients were in the product. That letter is in the 
record. It is attached to my statement. 

If you trust the FDA to preclear your labeling statements, you 
are not going to get any of this kind of information through. 

Mr. Sanders. The dilemma that some of us have is we do not 
necessarily trust the effectiveness of the FDA nor do we trust the 
honesty or integrity of some of these manufacturers. That is the di- 
lemma that we have to deal with. 

Mr. Towns. Thank you very much, Congressman Sanders. 

Congressman Horn. 

Mr. Horn. Mr. McNamara, what were your second and third 
points? 

Mr. McNamara. Mr. Horn, my second point was a concern that 
if one gives FDA the authority to preclear health-related claims, in- 
stead of after-the-fact authority to take action against false or mis- 
leading claims, you will prevent honest people from efficiently mak- 
ing statements that are truthful and not misleading. 

We have included in our statement examples of labeling positions 
FDA has taken that I think each of you will find highly question- 
able, if not repulsive, when you look at them. I think that it is ter- 
ribly dangerous of us to be setting up, at this time in our history, 



119 

when we are worried about government getting too big, a new bu- 
reaucracy. 

Think about what you are talking about. Every time anybody 
makes any new statement about the health or disease-related as- 
pects of any nutrient, he would need to get a new regulation before 
he could make the statement; and any time he would want to 
change it, he would have to do the same thing. 

Do we want preclearance of that kind in a free society, or do we 
say that if you make a false or misleading claim, the government 
can penalize you, and we set a high enough standard so that the 
government can effectively take action against people who do make 
fraudulent claims and frighten them from the market? 

Mr. Silverglade. That is the old system that gave us all these 
products. 

Mr. McNamara. Well, you know, you characterize them as being 
prolific. I don't know in terms of the total number of sales how 
many they are. I would take a fair guess — and I saw someone in 
the room who represents Centrum — I bet they sell in one State 
more than these products do in the whole country in the course of 
a year. 

There are honest and properly labeled products out there, and 
the problem with the government's remedy is it will prevent the 
honest purveyor from telling the truth efficiently. It will make him 
go through a hostile government bureaucracy and delay of years 
before the truth can be expressed. 

Truth should be a defense in any kind of action that the govern- 
ment sets up. Particularly in this era when we don't have enough 
money for government anyway, to be setting up new bureaucracies 
of preclearance, when we don't know if we can trust those people. 
It is not the way to be going. 

With respect to the remainder of your question 

Mr. Schiff. If my colleague would yield for a moment. 

Mr. Horn. Be glad to yield. 

Mr. Schiff. I appreciate that, and I ask him to yield to clarify 
something from the panelists on something I am getting confused 
on. 

Under the law today, as it exists with respect to labeling — and 
all I am talking about is labeling, meaning labeling claims actually 
making nutritional claims — is tne law any different between food 
and dietary supplements? 

In other words, is the law different between what you can say 
about bread or toothpaste than it is with respect to dietary supple- 
ments and labeling? 

Mr. Silverglade. 

Mr. Silverglade. Yes, it is, and the law was supposed to be the 
same for both foods and supplements, but the supplement industry 
won a 1-year exemption from the labeling law last fall in special 
legislation, so we now have a different law. 

The food companies have to go through the evil system Mr. 
McNamara has purportedly described that is so burdensome. They 
are living with this. They are selling their products. There is plenty 
of health information on food labels. 

And the Research Triangle Institute conducted a cost benefit 
analysis which said the health care savings from the provision of 



120 

reliable nutrition information on food labels may reach $100 billion 
over a 20-year period. So it is a good system that is working for 
the food industry and could establish a level playing field for the 
supplement industry. 

We care about this because a lot of these products are beneficial 
to health. We recognize that. We just don't want consumers to be 
confused. 

Mr. Schiff. I interrupted, but if I could just use the completion 
of my time. 

Mr. Silverglade say they are treated differently now under the 
law because the dietary supplement industry asked for an excep- 
tion. Mr. McNamara, do you agree with that? 

Mr. McNamara. Actually, your Honor, there has been a basis — 
excuse me, I am thinking of courts. 

Mr. Horn. Life tenure. 

Mr. Schiff. Life tenure is a promotion as far as I am concerned. 

Mr. McNamara. Sometimes I forget the forum in which I am 
present. I apologize. 

Mr. Schiff. A few of us in this body understand that. Go ahead. 

Mr. McNamara. Actually, going all the way back to the early 
1940's, FDA regulations recognized that dietary supplement and 
special dietary food products might properly, without becoming 
drugs, claim some information about their disease-related benefits. 

Let me call to your attention and quote from a regulation that 
has been in place since the 1940's. It is the definition in FDA's food 
regulations of foods for special dietary use, and it recognizes that 
a food for special dietary use may be promoted for uses including 
"supplying particular dietary needs which exist by reason of a 
physical, physiological, pathological, or other condition, including 
but not limited to the conditions of diseases, convalescence, preg- 
nancy, lactation, allergic hypersensitivity to food, underweight and 
overweight." 

Ever since the early 1940's, FDA has acknowledged in its regula- 
tions, but it has often not acknowledged in meetings, that if you 
are within that class, you may properly provide information of that 
sort as long as it is truthful and not misleading without triggering 
drug status. 

What they are now proposing to do to us, for the first time, in 
regulations proposed this year, is to say that one may not provide 
any of this kind of information, insofar as it relates a nutrient to 
a health- or disease-related condition, unless FDA first, by regula- 
tion, approves the particular representation. That is the concern we 
have here. 

Mr. Schiff. Mr. Chairman, if we have a second round, I will 
yield my time to Congressman Horn since I used up his. 

Mr. Horn. Actually, I have to leave for a floor debate, but, Mr. 
Chairman, if I can put in the record two sentences to reflect what 
FDA has protected us from. 

This is the 1887 registration for Coca Cola syrup, an extract, 
where they claimed, "This intellectual beverage, in temperance 
strengths, contains the valuable tonic and nerve stimulant from 
properties of the coca plant and kola — kola with a K — nuts, and 
makes not only a delicious, exhilarating, refreshing and invigorat- 
ing beverage expended from a soda water fountain, but a valuable 



121 

brain tonic and a cure for all nervous affliction, sick headaches, 
neuralgia melancholy, et cetera." 

Mr. Towns. If there is no objection, it will be included in the 
record. 

Congressman Payne. 

Mr. PAYNE. I just have a quick question, Mr. Silverglade. Earlier 
I asked Dr. Shank about the fact that many of the people who take 
these products are upper income, well-educated people that — you 
know, wise consumers. I kind of questioned that statement, though. 

But if the FDA proposal is implemented, what actions can we 
take to ensure, as I mentioned before, that the people from the 
lower end of the social economic scale receive the same information 
about the benefits of using dietary supplements? 

For example, the health claims for folic acid and its benefit, I 
would probably state that very few people in the category I men- 
tioned would even be familiar with what it is. 

Do you have any suggestions on that? 

Mr. Silverglade. We believe that the public health service 
should take a number of educational steps to reach disadvantaged 
and lower income consumers. We have stated, for example, that we 
believe that Americans should be able to purchase dietary supple- 
ments with food stamps. That would help, I think, address the con- 
cern that you are raising in part. There are a number of edu- 
cational steps to take. 

But deregulating the types of claims on labels is not going to give 
any consumers reliable, accurate information. 

Mr. Payne. Let me ask, Mr. McNamara, the statement that you 
made earlier about the fact that government is getting too big and 
it is overregulated and we just won't be able to handle this big gov- 
ernment, I think people were saying that around 1980. And they 
decided to fix up the S&L industry and they deregulated and with- 
drew and took people back. And we have, as you know, a problem 
of between $3 to $800 billion that we are going to have to deal with 
somewhere down the line. 

That does sound good, but a lot of times it just doesn't, for some 
reason, work. 

Let me ask you this quickly: What is your clients' objection to 
having their products being held to the same standard as regular 
food? 

Mr. McNamara. I think our objection, Mr. Payne, is not nec- 
essarily to the standard but to the procedure by which the stand- 
ard is applied. We object to preclearance, because it will take for- 
ever and it will run through a hostile agency. And we do not expect 
to get favorable, prompt, fair-minded responses within a reasonable 
period of time. 

We would encourage you to consider further and perhaps allow 
all food manufacturers to make truthful and nonmisleading state- 
ments as against the risk that FDA could take action against them. 

But there is a basis in the law for distinguishing between dietary 
supplements and other products. When the Nutrition Labeling and 
Education Act was passed, it authorized FDA explicitly to have a 
different standard and a different procedure for dietary supple- 
ments. FDA did not take Congress up on that. It chose not to waltz 



122 

at that dance. But it did, in fact, receive in the law from Congress, 
the authority to treat dietary supplements differently. 

And, historically, as I have shown you from FDA's own regula- 
tion defining foods for special dietary use, notwithstanding FDA's 
general principle over the years that one should not make disease 
claims for foods, FDA specifically allowed that kind of claim in the 
context of a food for special use dietary supplement. 

I believe if you sell a vitamin pill or a dietary supplement to pro- 
vide supplemental nutrition or additional nutrients, that you ought 
to be able to talk about it in a truthful and nonmisleading manner. 
If you make a misleading claim, let the government whack you; but 
let the government whack you for having done that. Don't require 
a law abiding company to go do that. 

Mr. Silverglaoe. Let's make sure that the process works before 
we throw the baby out with the bath water. 

Mr. Towns. Will the gentleman yield? 

I think it was stated earlier by FDA that we don't have that 
many people in the field. And I tnink what I am hearing you say 
is that vitamin C in an orange should be treated differently from 
vitamin C in a pill. 

Is that what you are saying? 

Mr. McNamara. What I am saying is that insofar as one is sell- 
ing a dietary supplement that exists to provide vitamin C, the 
consumer of that product has a focused interest in vitamin C. 

When you buy orange juice you may like it for the taste, as a 
breakfast drink, or whatever. If you buy vitamin C, you have an 
interest in vitamin C. If I go to the National Academy of Sciences 
monograph on vitamin C, I ought to be able to provide to my cus- 
tomers when I sell a dietary supplement, the information that is 
in the National Academy of Science's monograph on vitamin C. 
Under FDA's new procedure, I would not be able to do that without 
getting a regulation out of FDA first that authorizes me to do that. 

Now, I don't mind being told, "If your statement is false or mis- 
leading, Mr. Dietary Supplement Company, we are going to hit 
you." That is fine. That is the way the standard ought to be. But 
if I am a dietary supplement company selling vitamin C, and it oc- 
curs to me that my customers might be interested in what the Na- 
tional Academy of Sciences has to say, I ought to be able to repro- 
duce that in its entirety or with a fair balance and provide it to 
my customers without first needing to get a whole new regulation 
through the U.S. Food and Drug Administration. But that is what 
their process would require of me. 

The only thing FDA will allow a dietary supplement company to 
do so far is to talk about the relationship between calcium and 
osteoporosis. FDA may get around to doing it with folic acid. They 
haven't conceived of the fact that somebody who is selling vitamin 
C 

Mr. Silverglaoe. Excuse me. If I could interrupt. The system 
that Mr. McNamara is outlining is embodied in H.R. 1709, spon- 
sored by Congressman Richardson. That bill has been opposed — 
Mr. Schiff you questioned this — by the American Association of Re- 
tired Persons, the American Cancer Society, the American Heart 
Association, the Society for Nutrition Education, the American 
Home Economics Association, the Association of State and Terri- 



123 

torial Nutrition Directors, the Consumer Federation of America, 
the Consumers Union, the National Consumers League, the Amer- 
ican Dietetic Association, and the National Council on the Aging. 

Mr. Towns. I yield back. However the gentleman's time has ex- 
pired. 

Mr. Payne. That is right. The thing that bothers me is that we 
have an industry which brings $4 billion, legitimately, just with 
these products alone. 

It seems to me that when we have an industry that is strong, 
that has proven itself, the pharmaceutical industry in general and 
then you find that you get these shysters coming into an industry 
that is good, it tends, then, to discredit an industry that has had 
an excellent record for research and development and reducing the 
cost of health care, because medication prevents hospitalization in 
many instances and so forth. 

And I think the thing that is probably more disturbing to me 
than anything else is to see the products on the front there that 
do everything, you know, probably make my hair black again 

Mr. Towns. Or maybe create some hair for me. 

Mr. Payne. And to, you know, allow the industry to — I mean, the 
industry allows this to prevail. I know it is difficult to self-regulate 
because there are bad apples in every group. But I — Mr. McNa- 
mara, I know that you certainly couldn't sit there in good con- 
science — like "truth," you used that word a lot — and say these 
products and what they claim should be allowed to be on the shelf. 

Mr. McNamara. But, Mr. Payne, the point that I do try to make 
is that the law makes it illegal, so the Federal Food, Drug, and 
Cosmetic Act, any food, shall be deemed to be illegal if its labeling 
is false or misleading in any particular. 

The question, perhaps, you might ask to FDA is: Why are you 
not out after those products; and why were you instead out trying 
to bring unapproved food additive cases against black currant oil; 
or why were you sending out letters like I have attached to my 
statement that says it is misleading to tell how much of an ingredi- 
ent is in a product? 

FDA is misallocating its existing resources, and it ought to be 
working on actual safety-related concerns and on true fraud. And, 
for gosh sakes, don't start a new bureaucracy that requires 
preclearance of every health statement that anyone wants to make. 

Mr. Payne. I think I could agree with you that, in my opinion, 
in the past decade or more the FDA has been derelict in a lot of 
its responsibilities. As a matter of fact, I think the FDA became al- 
most a political organization in a lot of instances not dealing with 
substance. It seemed to be an industry that was defending things 
or looking the other way in some instances when they should not 
have. 

And I believe that it is hard to cleanse the agency in 6 months, 
but I agree with you that there has to be some restructuring in the 
agency in order for it to do as Ms. Stark said. People in America 
believe that whenever they pick up something, it is going to be all 
right because everyone understands or has heard about the FDA. 
So you can sleep because the FDA is awake, kind of thing. They 
used to say that about the National Guard. 



124 

But so I think that there was some problems with the FDA dur- 
ing the past. The fraud of some of these products is just uncon- 
scionable, really. And I couldn't agree more. 

Mr. Towns. The gentleman's time has long, long expired. 

Congressman Barrett. 

Mr. Payne. I was trying to get you some hair growth. 

Mr. Barrett. Thank you, Mr. Chairman. 

Mr. McNamara, can I, as a consumer, bring an action? Would I 
have standing to bring an action if I thought these food additives 
were mislabeled? 

Mr. McNamara. In terms of consumer law, that would be de- 
cided under your local State government for the most part. 

Mr. Barrett. Could I bring an action to have these taken off the 
shelf? 

Mr. McNamara. If you personally had been defrauded, under 
most State law, I believe you could have a remedy; if you had been 
hurt by a product, you would have a remedy. 

But the Federal Food, Drug, and Cosmetic Act right now is — for 
most provisions, is not enforceable by anyone other than the U.S. 
Attorney. 

However, for the new labeling provisions, the Federal law also 
may be enforced by the State governments. 

Mr. Barrett. Since you believe that the best source of action is 
to have the FDA do its job and go after the fraudulent products, 
would you be opposed under the Federal law to giving ordinary citi- 
zens or other producers of dietary supplements standing to bring 
injunctive relief? 

Mr. McNamara. I would say that that would be a novel idea that 
should be considered. 

Mr. Barrett. And would you support that? 

Mr. McNamara. As someone who represents a group, I would 
have to go back to my group. I can tell you what I would advise 
them. I understand the wisdom behind the idea. I would think that 
making it possible for individuals to test whether an irresponsible 
product has been sold is perhaps a better choice than needing to 
go through government preclearance for each and every label state- 
ment that one wants to make. 

And if you, as a Member of Congress, are weighing off the quids 
and the pro quos, that that is an issue, that is worth getting into 
the balance; it ought to be discussed. I don't think that the dietary 
supplement industry is afraid of its customers. Our customers are 
generally loyal customers who want the kinds of products that are 
being sold. 

And, you know, one may be defrauded into something occasion- 
ally in this world; but if a product doesn't work, you don't go buy 
it again. All right? And there is, I believe, no reason for our cus- 
tomers — for our industry to be terribly worried about our cus- 
tomers. 

Mr. Barrett. Mr. Silverglade or Ms. Stark, what would be your 
feeling on that? 

Mr. Silverglade. I think that system would only be good in con- 
junction with the preclearance system set up by the act. 

By itself, giving the consumers a private right of action would be 
woefully inadequate. We don't want people to try Kidney Flush and 



125 

find out that it's not working and have renal failure and then sue 
the company. 

With the L-tryptophan situation, there we had a contaminated 
batch of a product that killed 38 Americans, injured hundreds and 
hundreds of others seriously. There are many suits pending, and 
it's going to be tied up in the courts, as lawsuits often are, for dec- 
ades probably. 

Ms. Stark. I certainly don't oppose giving the consumer a right 
of action in this kind of case. The problem is that litigation is ex- 
pensive, and it becomes impractical for a single consumer to 
confront the entire dietary supplement industry. 

And you can see what kinct of influence that dietary supplement 
industry has in the country today. 

I want to respond to the point about preclearance and the oner- 
ous system that is being imposed by the new regulations. Prior to 
the NLEA, any of these therapeutic claims for any of these supple- 
ment products would have been treated as drug claims, and these 
products would have had to go through a much more rigorous 
preclearance system. They would have had to have been approved 
as new drugs. 

Under the NLEA, and what it did for foods and attempted to do 
for dietary supplements was treat them somehow differently and to 
allow limited numbers of health claims for these products without 
subjecting them to the premarket approvals for drugs. So I think, 
rather than saying that this is a brandnew onerous system, I think 
this is probably making the system much more lenient in terms of 
dietary supplements. 

Mr. Barrett. Mr. McNamara claims that the trigger mecha- 
nisms, the 90 days or 120 days, refer only to when the review must 
begin and not that anything must be completed within that time 
period. 

Is there a danger that you are going to be caught in a bureau- 
cratic never-never land? 

Ms. Stark. I think that always exists 

Mr. Barrett. If I am a guy trying to make a living, I don't want 
to develop a product and not be able to sell it because the people 
in Washington are not moving along. The worst thing is to have 
a bad product on the market. The second worst thing is to have a 
product that is languishing on a shelf somewhere in Washington, 
DC because no one is willing to take the time to find out whether 
or not it should be on the market. 

Ms. Stark. And I agree with that as well. And I think the FDA 
has shown a tremendous amount of responsibility in responding to 
those kinds of problems. They are already addressing the problem 
of folic acid supplements. 

Mr. Barrett. But shouldn't there be a time-certain date by 
which time the decision must be made? 

Ms. Stark. I don't think you can pin the agency down to a date. 
I think it would be better if you have a period of time. 

Mr. Silverglade. I think that the subcommittee should continue 
to exert its oversight so that the system works properly. That is 
certainly the honored tradition of this subcommittee to do that. We 
would, frankly, be spending our resources pushing FDA to decide 
what new health claims should be allowed more quickly, if you 



126 

don't have to fend off claims by the industry to get exempted from 
the law completely. 

Mr. McNamara. May I make an observation for the record? FDA 
has a long history of not living up to congressional deadlines for 
completing rulemaking proceedings. 

In the existing law, the existing Federal Food, Drug, and Cos- 
metic Act, there is a 180-day deadline, and they never meet it. And 
there is 180-day deadline for approving new regulations, and they 
never meet it. There is a 180-day deadline for issuing new color ad- 
ditive regulations; they never meet it. You put in a deadline for 
them to rule on labeling claims, that they don't want to approve 
in the first place, for an industry they don't like and they never, 
ever will meet it. And that's why you can't get the process ex- 
panded. 

Mr. Barrett. I understand what you are saying. A lot of these 
problems are created by this industry. 

Should we come up with the funding mechanism where the in- 
dustry would fund that? I think if the problem is that we don't 
have enough people in the FDA, which seems to be implicitly what 
you are saying, why shouldn't the industry, which doesn't seem to 
want to regulate itself, pay for that? 

Mr. McNamara. I think the first choice ought to be why FDA is 
spending so much money on going after black currant oil. If it re- 
allocated those sources to proper enforcement — if all the money 
that was spent on trying to 

Mr. Barrett. Let me cut you off with this question. Let me ask 
you this question. Let's say that we pinpointed where the money 
was to go and asked the industry to pay for it, what would be your 
position there? 

Mr. McNamara. I would have to consult with my client. I am 
doubtful that you can assure that the FDA will spend money wisely 
in a way that is going to make the system better. 

Mr. BARRETT. Isn't it hypocritical to criticize them for saying that 
they are not doing their job? 

Mr. McNamara. I don't think it is hypocritical to say— — 

Mr. Barrett. You are the one criticizing them. Isn't it hypo- 
critical for you to make that claim? 

Mr. McNamara. I am telling you and FDA that I believe they 
should be spending their money elsewhere. They have spent it 
poorly in their actions against dietary supplements. 

When the first circuit and the seventh circuit, in two unanimous 
Court of Appeals decisions, have characterized FDA's actions 
against dietary supplement products as "Alice in Wonderland," I 
think that question No. 1 ought not to be, "How do I give more gov- 
ernment money to the FDA?" I think question No. 1 ought to be, 
"Let's reconsider where FDA is spending its money." 

Mr. Silverclade. The FDA has 8,000-plus employees, and they 
spent less than 20 work years on all the dietary supplements. Ap- 
parently a lot of those work years were directed at your clients, be- 
cause they had a big problem. 

Mr. McNamara. I don't represent black currant oil. 

Mr. Towns. The gentleman's time has expired. 

Mr. McNamara. Look at the one page that I have attached 



127 

Mr. Towns. All of your material will be included in the record. 
And Mr. Schiff has also agreed that will happen. So no question 
about it. 

Mr. McNamara. FDA made an award to 61 FDA employees for 
chasing around on evening primrose oil. 

Mr. Silverglade. Maybe they spent 15 minutes per day doing 
it. 

Mr. Towns. Congressman Schiff. 

Mr. Schiff. Mr. McNamara, I want to come back. You have 
drawn this dire picture of what will happen if labeling by dietary 
supplements manufacturers has to go through a preclearance proc- 
ess with the FDA. My question is — and I understood what you read 
about historical context — my question is this: Suppose I manufac- 
ture bread, a food. OK? If I want to make certain nutritional claims 
about that bread, do I have to go through a preclearance process 
with FDA today? I think that is a yes or no question. 

Mr. McNamara. Under the new FDA regulations, which have 
been issued and finalized but which are not yet in effect, if one is 
selling bread and one wishes to make a claim that links a nutrient 
in the bread to a health or disease-related concern, one cannot say 
anything about it at all without first getting the approval of an 
FDA regulation. 

I think that is terrible. 

Mr. Towns. Is that yes or no? 

Mr. Schiff. Is that yes, if it goes into effect? Let's start with 
today. Today. Right now. This minute. If I manufacture bread and 
I want to make a nutritional claim, do I need this preclearance 
from the FDA that you indicate would be such a problem for die- 
tary supplements? 

Mr. McNamara. Well, the problem — and I am trying to be fair 
here, sir — is you must ask what a nutritional claim means. To use 
the magic lingo that FDA is using — and I am trying to mouth their 
words and to do it fairly here — under their new regulations, which 
are now final but not yet effective it will be illegal to put any state- 
ment either on the label or in labeling — and that includes not just 
stuff that wraps around the product Dut brochures that you mail 
separately, newsletters — it will be illegal to make any statement 
that links or relates a nutrient "to a disease or a health-related 
condition," unless one first gets a regulation authorizing the claim, 
a final regulation. 

Mr. Schiff. And you object — you object to that for foods as well 
as for dietary supplements; is that right? 

Mr. McNamara. I am not here representing a food company. I 
am here representing dietary supplement companies in Utah. I re- 
gret that that law was passed for the food industry in general. I 
think as they think about it and look back on it in the future, and 
find that they have useful things that they may want to say about 
some of their nutrients, and they then find out it takes 3 to 5 years 
to get that approved by FDA, they may regret it. 

But when the Nutrition Labeling and Education Act was passed, 
Congress explicitly provided that "dietary supplements of vitamins, 
minerals, herbs, and other similar nutritional substances" — and 
here I am repeating verbatim the Congress' phrase — could be regu- 
lated by FDA according to a different standard and procedure. 



128 

Our Senator, Senator Hatch, strongly stated on the record that 
he assumed FDA would do that. They did not. And they are now 
attempting to impose for supplements the same rule. 

One of my colleagues down the table says that what they are 
doing is creating a new opportunity for them. But that is not really 
true because, as I pointed out for dietary supplements, unlike con- 
ventional foods, there has been a regulation of FDA on the 
books 

Mr. Silverglade. That just applied to food service and hospitals. 
That is my interpretation. 

Mr. Schiff. Can we control the record? Mr. McNamara, I don't 
need repeated what you told us the first time. Mr. Silverglade. 

Mr. Silverglade. The answer to your question was yes. And be- 
yond that, let's just move on. 

Mr. SCHIFF. I will yield back to the chairman. 

Thank you. 

Mr. Towns. Thank you very much. And let me thank all of you. 
I guess you know by now that it is a pretty heated discussion. So, 
Ms. Stark, thank you. Dr. Johnston, Mr. McNamara, and Mr. 
Silverglade, thank all of you for your testimony. And may I assure 
you again that everything you have given us will be included in the 
record. 

Let me call the next panel. Mr. Cordaro from the Council for Re- 
sponsible Nutrition, followed by Ms. Hildwine from the National 
Food Processors Association, followed by Ms. Whittekin from the 
National Nutritional Foods Association. 

Will you please come forward. Before you sit, may I ask — as I ex- 
plained earlier, it is the custom of the Government Operations 
Committee to ask that witnesses who present testimony to the 
committee be sworn in. 

Please stand and raise your right hand. 

[Witnesses sworn.] 

Mr. Towns. Let the record show that the witnesses answered in 
the affirmative. 

Thank you very much. Please be seated. 

Thank you very much for being with us today. The full text of 
your statements will be inserted in the record. I ask that you sum- 
marize your statement in approximately 5 minutes. 

Let me begin with you, Mr. Cordaro. 

STATEMENT OF J.B. CORDARO, PRESIDENT, COUNCD, FOR 

RESPONSIBLE NUTRITION 

Mr. Cordaro. My name is J.B. Cordaro. I have been the presi- 
dent of the Council for Responsible Nutrition since 1982. CRN is 
an association of manufacturers of nutritional supplements, ingre- 
dients, and other nutritional products. CRN appreciates the oppor- 
tunity to participate in this hearing. 

There are few topics as timely as exploring the role that supple- 
ments can play in diet and health and their potential for prevent- 
ing disease and reducing health care costs. More than 100 million 
Americans use supplements. Thus, developing a comprehensive 
regulatory framework for supplements should be a national imper- 
ative. CRN urged Congress to make available safe, high-quality 
products. 



129 

CRN encourages Congress to establish a new process that pro- 
vides consumers access to information about the benefits of supple- 
ments and any potential risks. A growing body of scientific evi- 
dence indicates that increased intakes of specific vitamins, min- 
erals, and other nutrients can help protect against cancer, 
osteoporosis, cataracts, birth defects, and heart disease. 

Harvard University researchers indicate vitamin E can reduce 
the risk of heart disease in men by 26 percent and by 41 percent 
in women. 

Numerous studies have demonstrated a correlation between in- 
creased calcium intake and a reduced risk of fractures due to 
osteoporosis. 

Vitamin C has been shown to prevent stomach and other cancers, 
and beta-carotene has been shown to reduce the risk of lung can- 
cer. 

Studies have shown that women who consume 0.4 milligrams of 
folic acid can cut the risk of spina bifida and other neural tube 
birth defects by at least 60 percent. 

Americans might get these nutrients through their diets, but the 
fact is most people don't properly select their foods. The most com- 
prehensive national survey showed that not 1 person out of more 
than 21,000 got 100 percent of the recommended dietary allowance 
for the 10 basic nutrients from diet alone. 

Certain risk groups are particularly vulnerable. Of senior citi- 
zens, 25 percent get insufficient levels of vitamins A and C, iron, 
and calcium. Pregnant women have a very high nutrient intake 
need that is rarely met by diet alone. Children from low-income 
families and even healthy young high school and college students 
often fail to meet their nutrient needs from diet alone. 

On the positive side, there is a long history of safe use and 
consumer acceptance of dietary supplement. On the whole, the sup- 
plement industry has an enviable safety record. Problems that 
have arisen, such as with the essential amino acid L-tryptophan, 
have generally been due to manufacturing errors. 

Advice to members to pull L-tryptophan from the market oc- 
curred as soon as we learned of the contamination problem, with- 
out waiting for an FDA formal recall request. CRN has rec- 
ommended dosage limits and cautionary labels for vitamins A, B- 
6, and for niacin. 

CRN adopted good manufacturing practices in 1986 and has been 
working closely with the U.S. Pharmacopeia to set quality stand- 
ards. Finally, CRN is also working with various State attorneys 
general to find an appropriate way to address the iron issue. For 
example, Dr. Dickenson, myself, and my staff are meeting with Ms. 
Stark on August 3 to address the specific problem that she raised. 

In the past, FDA has tried to mandate labels saying supplements 
are unnecessary; sought to restrict the quantity of nutrients in sup- 
plements to no more than 150 percent of the RDA; proposed to clas- 
sify most vitamin products as drugs; and has tried to ban supple- 
ments by classifying them as food additives. 

Because of FDA's perspective on supplements, legislation is ur- 
gently needed. CRN supports proposals by Senator Orin Hatch and 
Congressman Bill Richardson. 



130 

CRN believes that there should be a comprehensive review of the 
safety of supplements. All products with a history of safe use 
should be classified safe. 

CRN believes all supplements should be required to adhere to 
appropriate quality standards and good manufacturing practices. 

CRN believes health claims for dietary supplements, as well as 
conventional foods, should be allowed if a nutrient-disease relation- 
ship is recognized by credible public health organizations, or if a 
significant number of qualified experts agree that the evidence ade- 
quately substantiates the proposed claim. 

I am almost through, Mr. Chairman. 

CRN believes supplement labeling should fully disclose informa- 
tion about the product's benefits, its ingredients, expiration dates, 
and any appropriate cautions. 

Finally, CRN believes it is essential for Congress to create a new 
Center for Dietary Supplements and a Supplement Advisory Com- 
mittee with expert panels to help focus FDA's attention to the role 
of dietary supplements in the diet. 

Thank you, Mr. Chairman. 

Mr. Towns. Thank you. 

[Note. — To reduce publication costs, the subcommitee has omit- 
ted from the record a booklet entitled, "Vitamin Issues, Rationale 
for Dietary Supplement Legislation," from the Council for Respon- 
sible Nutrition. A copy of the booklet may be found in the sub- 
committee files.] 

[The prepared statement of Mr. Cordaro follows:] 



131 



STATEMENT OF J. B. CORDARO 

PRESIDENT 

COUNCIL FOR RESPONSIBLE NUTRITION 

to 

U. S. HOUSE OF REPRESENTATIVES 

SUBCOMMITTEE ON HUMAN RESOURCES AND 
INTERGOVERNMENTAL RELATIONS 

GOVERNMENT OPERATIONS COMMITTEE 

HEARING ON 

FDA's REGULATION OF DIETARY SUPPLEMENTS 



July 20, 1993 



132 



CRN 

The Council for Responsible Nutrition (CRN) is a trade association of manufacturers 
of nutritional supplements, ingredients, and other nutritional products. CRN is 
dedicated to helping improve the environment for consumers to appreciate the need, 
benefits, safety, and economy of its members' products. 

Specifically, CRN's missions are: 

• to increase the awareness of the appropriate dietary role for nutritional 
supplements, ingredients, and other nutritional products by utilizing 
authoritative and sound scientific, social, and economic information: 

• to enhance the credibility of the nutrition industry's message through a 
proactive communications strategy; 

• to protect and promote the interest of the nutritional supplements, ingredients, 
and other nutritional products industry in the legislative and regulatory 
arenas; and 

• to promote CRN members' interests through services, activities, and events. 



J. B. Cordaro 

J. B. Cordaro has been president of the Council for Responsible Nutrition since 1982. 
Cordaro has 28 years experience in domestic and international food, nutrition, and 
agricultural activities, including senior positions with the Food Safety Council; the 
congressional Office of Technology Assessment; and the U.S. State Department's 
Agency for International Development. He also served as the OTA Board staff 
representative for Senator Hubert Humphrey (D-MN). He is a graduate of Loyola 
New Orleans with a B.S. degree in government, economics, and philosophy and 
attended the Georgetown University Graduate School of Foreign Service. He received 
his advanced degree in agricultural economics, with a special emphasis on nutrition 
policy planning, from Cornell University. 



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My name is J. B. Cordaro. I am the President of the Council for Responsible 
Nutrition, an association of the manufacturers of nutritional supplements, 
ingredients, and other nutritional products. 

I thank the Chairman and the other members of the Subcommittee on Human 
Resources and Intergovernmental Relations of the Government Operations Committee 
for calling this important oversight hearing and for the opportunity to participate. 

CONSUMERS NEED A NEW REGULATORY FRAMEWORK 

Congress has begun the daunting task of reforming America's health care system. 
There are few topics as timely as the role dietary supplements can play in 
maintaining good health and preventing chronic disease. A powerful wave of new 
scientific evidence proclaims the link between nutritional supplements and disease 
prevention. 100 million users of dietary supplements assert that it is long past time 
for the government and industry to join together to ride that wave to a healthier 
future for all Americans. 

Given the importance of disease prevention and health maintenance, and the 
scientific evidence pointing to the significant role dietary supplements can play in 
that regard, we cannot waste time. We must develop a rational, comprehensive 
regulatory framework for dietary supplements. 

That framework must ensure that consumers will continue to have access to safe, 
high quality products and will be provided information about expected benefits as 
well as any potential risks necessary to make educated decisions. 

VITAMIN USERS 

More than 100 million Americans responsibly use vitamins, minerals and other 
nutritional substances to supplement their diets. Many use supplements every day 
for most of their lifetime. Recent surveys show that more and more health 
professionals, doctors, nurses and dietitians, are using nutritional supplements. A 
recent Medical Tribune survey revealed that 8 out of 10 doctors who responded to the 
survey take vitamin E to protect against heart disease. Nearly 60 percent of 
dietitians polled in a Washington state study use nutritional supplements, and a 
survey of over 1,700 nurses indicated that 38 percent use multivitam i ns. 

VITAMINS ARE SAFE 

Vitamin and mineral supplements are a safe, beneficial and economical way to get 
optimal amounts of the micronutrients necessary for general good health and to help 
protect against serious chronic diseases. 



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Nutritional supplements of vitamins and minerals have a 70-year history of safe use 
by the American public. This use dates back to the period when vitamins were first 
discovered in the early part of this century. Herbal supplements have an even longer 
history of use, in some cases dating back to the ancients. 

RAPIDLY EMERGING SCIENCE SUPPORTS SUPPLEMENTS 

There is a convincing and growing body of scientific evidence indicating that 
increased intakes of specific vitamins and minerals can play an important role in 
protecting against such diseases as cancer, osteoporosis, and heart disease and 
chronic conditions such as cataracts. For example: 

In recent studies conducted at Harvard University School of Public Health and 
Harvard Medical School, vitamin E supplements were shown to reduce the risk 
of heart disease by 26 percent for men and 46 percent for women. 

Numerous studies conducted within the past 10 years demonstrate a 
correlation between increased calcium intake and reduced risk of osteoporosis 
and hip fractures. 

Vitamin C has been shown to prevent cancers of the stomach, esophagus and 
oral cavity, and beta-carotene has been shown to reduce the risk of lung 
cancer. 

According to a meta-analysis of vitamin C and breast cancer studies. 16 
percent of breast cancers in postmenopausal women could have been prevented 
with increased intake of vitamin C. 

In addition, adequate nutrition is essential in the fight to reduce infant mortality, 
prevent birth defects, and guarantee healthy development. The United States of 
America has one of the highest infant mortality rates in the developed world, and 
improved prenatal care that addresses nutritional adequacy can help bring that 
down. The incidence of neural tube birth defects, such as spma bifida, could be 
reduced by more than 60 percent if all women capable of becoming pregnant 
consumed 0.4 mg of folic acid per day. 

AMERICANS NEED MORE NUTRIENTS 

But the simple fact is that most Americans are not getting enough of the nutrients 
they need from the foods they eat. The most comprehensive national survey showed 
that not one person out of more than 21.000 got 100% of the Recommended Dietary 
Allowance for 10 basic nutrients from diet alone. Only three percent of those 
surveyed consumed the recommended number of servings from the four food groups 
on each of the three days surveyed. In the most recent United States Department 

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of Agriculture nationwide survey of food consumption conducted in 1988. the nutrient 
intake profile had not improved much. More than 70% of men and 80% of women 
failed to get even two-thirds of the RDA for one or more nutrients. 

Certain risk groups are particularly vulnerable: 

A recent national study of senior citizens revealed that 25 percent receive 
insufficient levels of vitamin A, vitamin C, iron, or calcium. Senior citizens do 
not metabolize nutrients well, have suppressed appetites, and often take 
medications that impair their nutritional status. 

Pregnant women have very high nutrient intake needs that are rarely met 
by diet alone. The dietary habits of pregnant women not only affect their own 
health, but can possibly impair the development of their child. 

Children from low-income families and even healthy young high school and 
college students often fail to meet nutrient needs from diet alone. 

Infants with inadequate intakes of iron are at risk of impaired mental and 
behavior development. Studies demonstrate that siblings who had better 
nutritional intake in the first year of life are more intelligent, perform better 
in school, and have fewer behavior problems. 

Dieters are also at risk. A study of eleven popular weight reducing programs 
found that the diets failed to provide adequate levels of calcium, iron, zinc, 
thiamin, vitamin B-6 and vitamin B-12. The popular trend toward reduced fat 
diets makes people particularly vulnerable to low vitamin E intakes. 

Smokers have been found to have decreased levels of vitamins C and E. 
Studies show that smokers need to consume higher amounts of these vitamins 
to meet serum levels of nonsmokers who are consuming RDA levels. Several 
countries, including the United States, officially recommend that smokers 
increase their intake of vitamin C and have set the daily recommendations of 
vitamin C for smokers at a higher level than for nonsmokers. 

We pay a heavy price for these nutritional shortfalls. It is a price measured not only 
in health care dollars expended to treat preventable illness, but also in the damage 
done to the health and well being of millions of Americans and their families. It is 
a price made all the more dear because we have the knowledge and means to do 
something about these nutritional shortfalls and to make sure that Americans have 
access to the protective amounts of nutrients that will help shield us against many 
chrome diseases. 



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HISTORICAL VIEW ON SUPPLEMENT REGULATION 

Both Congress and the FDA have a long history in dietary supplement regulation. 
In the Food, Drug and Cosmetic Act of 1938 Congress established under Section 
403(j) a category of foods called "foods for special dietary use.'' This category included 
nutritional supplements, infant foods, foods for diabetics, low and reduced sodium 
foods, and medical foods. 

According to Section 403(j) of the Act, the label of a special dietary food must provide 
"such information concerning its vitamin, mineral, and other dietary properties as the 
Secretary determines to be, and by regulations prescribes as, necessary in order fully 
to inform purchasers as to its value for such uses." 

Senator Royal S. Copeland (D-NY), the sponsor of the bill that became the Food, Drug 
and Cosmetic Act, explained that the purpose of section 403(j) was to assure 
consumers access to information about the latest advances in nutritional science. In 
1934, Copeland recognized that it was "essential to the well-being of the public that 
provisions be made to keep abreast of [nutritional science] developments and to 
require informative labeling to accord with the facts as they are uncovered from time 
to time." 

The FDA, however, has followed a very narrow interpretation of this congressional 
mandate. According to the FDA, a mere listing of the vitamin and mineral content 
of nutritional supplements is enough to "fully inform purchasers" of their value. 

CRN believes the agency and the industry have not yet begun to truly explore the 
kinds of information needed on labels or in labeling to fully accomplish the purpose 
of 403(j). We do not believe the job of regulating nutritional supplements can be 
considered complete until product labeling contains all of the information consumers 
need in order to understand how to appropriately use each particular product. 

FDA AUTHORITY ADEQUATE 

FDA has full authority over the safety of all ingredients of food, including dietary 
supplements. History suggests that FDA's authority has proven adequate in 
protecting the basic safety of the food supply. FDA's approach to supplements, 
however, has historically been negative. Where dietary supplements are concerned. 
FDA repeatedly has attempted to overstep its statutory- authority. 

FDA has tried to mandate labels for supplements that would declare them 
unnecessary. 



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In 1973, FDA tried to restrict the quantity of nutrients permitted in 
supplements to no more that 150 percent of the RDA and tried to classify 
vitamins as drugs. 

On several occasions, FDA has tried to ban many supplements by classifying 
them as food additives and withdrawing them from the marketplace on the 
grounds that they have not been precleared by FDA. 

The courts and Congress have not supported these efforts. In 1976, Congress passed 
the Rogers-Proxmire vitamin and mineral amendments to the Food, Drug and 
Cosmetic Act (Section 411). This prevented FDA from classifying vitamins as drugs 
and unreasonably restricting supplement formulations. Just last year, two U. S. 
Courts of Appeals rejected FDA's overbroad interpretation of the food additive 
provision as applied to dietary supplements. 

NUTRITION LABELING AND EDUCATION ACT OF 1990 (NLEA) 

FDA's most recent actions on dietary supplement regulations relate to the Nutrition 
Labeling and Education Act of 1990 (NLEA). In this landmark legislation. Congress 
recognized the health benefits of nutritional improvements in the American diet and 
established the ground rules governing health messages for particular nutrients. One 
of NLEA's objectives was to provide more information about nutrients and their 
disease prevention role so consumers could optimize their intake of various nutrients. 

The NLEA particularly recognized the role of nutritional supplements and directed 
the FDA to consider whether unique standards and procedures for health claims are 
needed for supplements. Senator Hatch explained that special treatment might be 
warranted for supplements because "by their very nature, supplements must be 
marketed so that the consumer is informed of the health and disease-prevention 
benefits that may be conferred." Congress also directed the agency to evaluate these 
four health claims, specifically for dietary supplements: 

- Folic acid and neural tube defects 

- Antioxidant vitamins and cancer 

- Zinc and immune function in the elderly 

- Omega-3 fatty acids and heart disease 

FDA has firmly declined to establish separate procedures for approving health claims 
for dietary supplements. Moreover, FDA has so far not approved any of the four 
dietary supplement claims specified in the NLEA despite the increasing scientific 
evidence linking these nutrients to disease protection. In fact, FDA has specifically 
denigrated the role of supplements by approving claims only for foods which are 
naturally high in vitamin C, beta-carotene, dietary fiber, or soluble fiber, while 
rejecting those same claims for dietary supplements providing the same nutrients. 



138 



with no scientifically valid reasons for doing so. Fruits, vegetables, and grains which 
naturally provide a mere 10% of the Daily Value for these nutrients may bear a 
health claim saying that diets rich in these foods may help protect against cancer and 
heart disease. However, fortified foods or dietary supplements providing more 
generous and appropriate amounts of the same nutrients would be forbidden to bear 
the claim. 

FDA has said it plans to approve a health claim for folic acid relating to the 
prevention of neural tube defects, and to suggest a fortification plan for delivering 
more folic acid through the food supply. However, it has now been 10 months since 
the issuance of the Public Health Service recommendation regarding folic acid, and 
in that time about 2,000 babies have been born with spina bifida and anencephaly. 
A large proportion of these birth defects might have been prevented by more timely 
action to inform women of the importance of an adequate intake of folic acid before 
and after conception. 

As a result of FDA's policies, manufacturers are prevented from communicating 
scientific information about the relationship between diet and health. Consumers are 
left to make decisions about nutritional adequacy based on anecdotal information or 
the latest nutritional fad. Consumers are effectively denied access to accurate and 
truthful scientific information about the role dietary supplements can play in disease 
prevention, and about the proper uses of supplements. Clearly, this is not in the 
public interest and Congress must act to correct this situation. 

NEXT STEPS 

Where does that leave us and what do we need to do? 

On the one side, supplements have a long history of safe use and consumer 
acceptance. Further, growing scientific evidence exists on the importance of these 
substances to disease prevention. 

On the other, we have FDA's repeated attempts to regulate dietary supplements as 
drugs or food additives and an unwillingness to recognize and support the role of 
dietary supplements in helping people get the nutrients they need to promote growth, 
maintain health, and prevent chronic disease. 100 million consumers are caught in 
the middle. Congress has an opportunity to assert a leadership role in resolving this 
matter. 

As tortured as the history of dietary supplement regulation is. there can be little, if 
any, disagreement that regulations should: 

1. guarantee continued consumer access to safe products manufactured to 
high quality standards; and, 

2. ensure that consumers are fully informed about the benefits, uses and, 
where appropriate, any risks of dietary supplements. 



139 



Safety. Assuring consumers of the safety and quality of dietary supplements is 
fundamental. CRN's member companies are committed to selling only safe products 
of the highest quality. On the whole, the dietary supplement industry has an 
excellent record in this regard -- one any segment of our food system would envy. 
Those problems that have arisen, for example with L-tryptophan, have generally been 
the result of isolated manufacturing errors and are no different from similar problems 
that have occurred with other foods. 

So that the entire industry meets the same high standards to which CRN member 
companies are committed, CRN supports legislation that will ensure the public of the 
safety and quality of these products. 

Information. It is equally fundamental that consumers should have access to 
information about the nutritional value of the dietary supplements they purchase. 
At present, FDA's overly restrictive interpretation of the NLEA prevents 
manufacturers of dietary supplements from communicating to consumers anything 
about the role of particular nutrients in reducing the risk of disease. *The only 
exception is calcium. ) Manufacturers cannot even tell consumers about the Public 
Health Service's recommendation that women of child-bearing age should take a folic 
acid supplement to substantially reduce the risk of neural tube defects. 

To address this problem, CRN supports legislation that would achieve three goals. 
First, allow supplement makers to inform consumers about the recommendations of 
recognized public health authorities. Second, allow supplement makers to provide 
consumers the same information as food companies can. Third, allow supplement 
makers to disseminate educational material about current nutrition research, so long 
as they do not use that information to make unsubstantiated claims for their 
products. 

What consumers need is a new regulatory framework for dietary supplements that 
recognizes that these products are used exclusively for health and nutrition purposes. 
This unique character of dietary supplements adds an additional dimension to the 
safety and labeling issues that must be addressed by these regulations. 

FAIR AND EVENHANDED ENFORCEMENT 

Before I outline what the Council for Responsible Nutrition sees as the building 
blocks for this new regulatory framework, I want to say a few things about one 
additional element that must be present if we are truly to serve the public interest. 
That element is fairness. Many in this industry, and I believe in the Congress and 



140 



among consumer advocates, believe that at times the FDA has not dealt with dietary 
supplement issues in a fair and even handed way. The record is replete with 
examples to support these perceptions. 

The agency refused to allow supplement claims for nutrients recognized in 
conventional food claims. 

FDA attempted to regulate supplements as food additives while virtually 
refusing to use the legitimate authority it has to regulate these substances as 
food and to protect the public against false claims. 

In the same month that FDA's Deputy Commissioner Taylor was reassuring 
the industry and the public that the vast majority of supplements pose no 
safety or health problems, FDA issued an Advance Notice of Proposed 
Rulemaking that suggests an intent on the part of the agency to severely 
restrict access to these substances. 

Such a regulatory approach serves no useful purpose. More importantly, it squanders 
valuable resources that should be devoted to promoting the public health rather than 
attacking the supplement industry. It is essential that the FDA begin to view dietary 
supplements, along with conventional foods, as equally valuable tools in delivering 
improved health to the American people. 

SELF REGULATION 

The members of the Council for Responsible Nutrition are dedicated to enhancing the 
public health by promoting nutritional excellence. CRN's membership has developed 
and ratified a Code of Ethics for the Council and its members. The Code affirms that 
CRN members 

"recognize their duty to provide the public with safe and beneficial 
supplements, manufactured to high quality standards, and to ensure 
that consumers are provided with the accurate information that need to 
make informed choices." 

This is why CRN has recommended dosage limitations and cautionary labeling on 
products, such as vitamin B-6, niacin and vitamin A. that could cause harm if 
recommended dosage levels are abused. 

This is why L-tryptophan supplements were pulled from the market voluntarily, as 
soon as the industry learned of the contamination problem, without waiting for a 
formal recall request by FDA. 



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CRN understands that development and implementation of appropriate quality 
standards for nutritional supplements ultimately benefits both industry and 
consumers. That is why CRN members adopted Guidelines for Good Manufacturing 
Practices for nutritional supplements in 1986 and is cooperating with the U.S. 
Pharmacopeia in developing quality standards. And it is why we have been working 
with Congress, and would like to work with FDA, to develop a new regulatory 
framework that serves the public interest. 

1993 DIETARY SUPPLEMENT LEGISLATION 

We commend Senator Hatch, Congressman Richardson, and their dozens of co- 
sponsors for their leadership and support with their Dietary Supplement Health and 
Education Act of 1993 bills. The legislation encompasses those components necessary 
to construct a rational, coherent regulatory framework for dietary supplements. 

Rather than address the legislation in its specifics, we will limit our presentation to 
those key components that are essential if we are to succeed in building our new 
regulatory framework. 

DEFINITION OF DIETARY SUPPLEMENTS 

The definition of dietary supplements should include vitamins, minerals, herbs, 
amino acids, and other "dietary" ingredients, i.e., ingredients intended for use to 
supplement the diet by increasing total dietary intake. It would include supplements 
sold in forms that have the characteristics of conventional food, so long as such 
substances were clearly labeled as intended for use to supplement the diet. This 
definition, however, would exclude chemical entities not commonly found in the food 
supply. 

SAFETY 

The starting place for any system for assuring the safety of dietary supplements 
should be the establishment of an up-to-date, comprehensive review of dietary 
supplements. As indicated above, most of these substances have a long history of 
safe use, including foreign data. Unless it can be scientifically shown that an 
ingredient may result in injury or illness under the conditions for use prescribed in 
its labeling or advertising or under such conditions of use as are customary or usual, 
the product should remain on the market. All dietary supplements should be 
excluded from the food additive definition. 



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Obviously, such a review must be conducted by unbiased, objective substance-specific 
expert panels. Any dietary ingredients currently recognized as GRAS -- generally 
recognized as safe -- or for which there is an approved food additive regulation should 
be presumed safe when used in accordance with the preexisting regulation. No 
product for which there is a history of safe use in the United States or abroad should 
be classified as unsafe, unless there is a demonstrated risk of harm from toxicological 
or other clinical studies. All dietary supplements now sold in the United States 
should continue to be sold pending completion of this review, unless of course they 
were found to be adulterated or mislabeled under other relevant regulatory 
provisions. 

New ingredients that a manufacturer desires to introduce to the market should be 
required to complete a safety review. This review should be conducted under the 
same standards as for existing products, but the regulations must include clear 
deadlines for completion of any such review. 

Where there is an objective scientific indication of safety concerns, these concerns 
should be systematically addressed. FDA should be allowed to establish dose 
limitations, require adverse reaction labeling, or remove or preclude the product from 
the market, depending on the findings of the expert panel. 

QUALITY STANDARDS 

All supplements should be required to be clearly labeled regarding adherence to 
quality standards or general manufacturing practices adopted by USP for the 
particular substance involved. Unless a supplement meets those standards and/or 
is manufactured according to such practices its label would be required to state 
clearly that it does not meet USP standards. 

HEALTH CLAIMS 

Claims for dietary supplements and conventional foods should be judged according 
to the same standards. That standard, however, must be clarified to provide that 
"significant scientific agreement" is presumed to exist whenever: 

the claimed relationship is recognized to exist by a public health 
organization that is accepted as a credible source of information about 
diet and health. This should include at least the Center for Disease 
Control and Prevention and any of the National Institutes of Health. 



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a significant number of qualified experts agree that publicly available 
peer-reviewed studies adequately substantiate that the claimed 
relationship exists, taking into account the qualifications included in the 
claim and the probable public health benefits that would result from 
recognition of the claim. 

All claims for which the Nutrition Labeling and Education Act requires FDA 
authorization should be reviewed initially by an unbiased, objective substance specific 
expert panel. In addition, any claims that have been authorized for conventional 
foods should be permitted for supplements, unless there is significant scientific 
agreement that the dietary ingredient will not provide the same benefits if consumed 
in a supplement. 

DIETARY SUPPLEMENT LABELING 

Dietary supplement labeling should contain full information about the identity of the 
product, including the name and quantity of each ingredient, and in the case of herbs, 
the part of the plant from which the ingredient is derived. Also, the product should 
bear an expiration date. 

The fact that consumers use dietary supplements for specific health and nutrition 
reasons requires that they be provided the information necessary to make informed 
choices about the products they use. Dietary supplement labeling should be 
permitted to provide accurate, scientifically substantiated information regarding its 
dietary benefits, as follows: 

the physiological function of the ingredient; 

the effects of inadequate and/or excessive intakes; 

food sources and usual dietary intakes; and 

current reliable scientific research concerning the relationship between 
consumption of the nutrient or other dietary ingredient and the 
maintenance of good health. 

ADMINISTRATP/E IMPROVEMENTS 

These are the key components. Further, CRN believes that consideration should be 
given as well to a number of additional mechanisms that would promote the overall 
objectives set forth above. 



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Congress should: 

• Create a new Center for Dietary Supplements in FDA and establish an 
Advisory Committee for Dietary Supplements. This should help focus the 
agency's attention on promoting the public health aspects of supplement use 
at the same time it protects public safety. 

• Provide more expeditious judicial review of agency actions and clear statutory 
deadlines for decisions should be provided. This will promote the fair and 
evenhanded enforcement of regulations that is essential for the development 
and expansion of this important consumer products industry. 

There is much to be done and the stakes are far too high for us to be delayed by 
bureaucratic inertia or to be distracted by outdated prejudices and past grievances. 
We have the science and we know with greater certainty every week the enormous 
potential for disease prevention and health maintenance. 

CRN bebeves and hopes that new legislation will be passed by this Congress to better 
define the appropriate regulation of dietary supplements. We call on this 
Subcommittee to exercise its oversight authority to assure that both the FDA and the 
industry move expeditiously and cooperatively to implement the new approaches 
mandated by Congress or to see that the recognized problems are addressed to the 
extent possible even in the absence of new legislation. 

100 million consumers are seeking to improve their health and well being. Congress 
should ensure that they have the products and the information to support their 
endeavor. 

Thank you. 



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CHICAGO TRIBUNE 



Op-Ed Page 



July 11, 1993 



Squelching of facts 
may be hazardous 
to your health 

A free society starts from the assumption that the 
way to reach the truth is to let fools, villains and 
prophets all have their say, trusting listeners to weigh 
the claims and make up their own minds. The 
federal Food and Drug Administration, however, 
thinks it is better for Americans to hear nothing at 
all than to run the risk of hearing anything that isn't 
so. 

Impatient with health claims made for dietary 
supplements, it has launched a campaign supposedly 
aimed at fraud that will actually silence truth. An 
agencv charged with protecting health will put it at 
nsk bv keeping consumers uninformed of revelations 

Stephen Chapman 



that can save lives. 

Newspapers, magazines and broadcasters have all 
done us the favor of reporting the new discovery that 
high daily doses of Vitamin E may reduce the nsk of 
heart disease. They have also noted medical findings 
that substances known as omega-.} fatty acids mav 
likewise confer protection. 

If the FDA gets its way. though, the companies 
marketing vitamins and other supplements won't be 
allowed to advertise what Peter Jennings is free to tell 
>ou. A nutritional labeling act passed in 1990 and 
now being implemented allows health information 
only if it reflects "significant scientific agreement.'' 
Labels containing this sort of material must be 
approved in advance by the agencv. 

So far. the FDA has found only two which it 
thinks pass the test. Calcium supplements may note 
the value of their product in preventing osteoporosis, 
and the agencv expects to allow the information that 
folic acid reduces some kinds of birth defects — 
something the government's Public Health Service 
has been trumpeting for nearly a year. 

\nd what about the experts who have concluded 
that Vitamin E mav head off heart trouble or that 
beta-carotene may save you from cancer? You 
-houldn t reallv clutter your mind with this kind of 
tnvia until Uncle Sam decides those experts are 
absolutely right. 

Once the studies have been done and re-done to 
jcath. once evervone on earth agrees that a particular 
supplement is good for %ou. then the makers of that 
supplement can publicize this benefit to sell their 
product. I'ntil then, thev d better shut up. 

If the FDA policy has the unfortunate drawback 
that \ou don t find out about the value of Vitamin E 
until after \our fatal coronary, well, that's a price you 
should be readv to pay. The agency and the law 
pretend the onlv nsk is taking supplements vou don t 
need, when there is an equal nsk in not taking 
supplements <.ou do need. 



But people won't know about the latter c — 
unless someone informs them, a process that is not 
free. The best wav to assure that information gets out 
quickly is to allow its transmission by the people who 
stand to profit The average consumer doesnt read 
the Journal of the American Medical Associ at ion to 
keep abreast of the latest dimral trials. If she can't 
get the news about Vitamin E at her local health 
food store, she may not get it all- 
in some cases, the FDA's logic is even loonier. 
Some foods contain "anu-owdanrs" like Vitamin E 
and C and beta-carotene, which y j tmwti have found 
may prevent cancer. So health claims will be - 
permitted for foods with these nutrients— but not for 
supplements. The FDA's explanation is that* 
doesn't know if the boon to health comes from the 
anti-oxidants or something ebe in these foods, since 
studies have reached different conclusions. 

But if there's evidence that the credit should go to 
the anti-oxidants alone, why not let su pok rn e nt 
makers note this fact and let health-consaous 
Americans decide how they want to get their 
Vitamin C? After all, citrus interests can be counted 
on to note the potential superiority of their product 
The problem here is that rather than concentrate 
on fraudulent claims — which it can alread y stop by 
taking the culprits to court — the agency is a nw i nng 
honest ones. Besides possibly running afoul of the 1st 
Amendment, it treats consumers like naive children 
helpless to look out for themselves. _ 

A measure introduced in Congress woul d reve rse 
the bias of the existing law, allowing supplement 
labels to provide any health information that is 
truthful and not misleading. Instead of presuming 
almost all of these claims to be guilty until proven 
innocent, requiring them to pass inspection by a 
federal censor, the proposal would force the FDA to 
show that something is wrong with them before 
taking action. 

The agency worries that without its vigilance, 
someone, somewhere, wul be lured into a mistaken 
purchase. But mistakes can't be purged from any 
svsiem featuring human beings. Allowing honest 
health information on supplements may not assure 
perfect knowledge, but it wul prevent perfect 
imiorance. 



146 



MEDICINE 



Vitamin E for a Healthy Heart 

Two new studies suggest supplements can pay off 



Preventing heart disease 
isn't easy. As health ex- 
perts never tire of remind- 
ing us, it requires giving up 
cigarettes, exercising vigorous- 
ly and sticking to a lean, 
plant-based diet. But additional 
insurance may come in pill 
form. Researchers have long 
suspected that vitamin E and 
theotherso-called antioxidants 
(beta carotene and vitamin C) 
could help protect arteries 
from the ravages of cholesterol. 
Two new studies suggest they're right — at 
least about vitamin E. The studies, report- 
ed in last week's New England Journal of 
Medicine, found that among 120,000 peo- 
ple, those who took vitamin E supplements 
suffered about 40 percent less heart disease 
than those who didn't. Cause-and-effect 
have yet to be proven, but the new findings 
suggest vitamins could become a potent 
weapon against the nation's leading killer. 
Researchers have known for some time 
that high cholesterol isn't the whole story 
on heart disease. Dr. Daniel Steinberg, a 
cardiologist at the University of California, 
San Diego, theorized more than a decade 
ago that oxidation — the chemical reaction 
that causes metal to rust and butter to 
turn rancid — can also damage coronary 
arteries. Oxidation involves 
molecules called free radicals, ^^^^™ 
which crop up in our bodies as 
oxygen interacts withcells. Un- 
like a normal oxygen molecule, 
in which each atom is ringed by 
pairs of electrons, a free radical 
carries one electron that lacks a 
mate. Oxidation occurs when a 
free radical kidnaps an elec- 
tron from a neighboring mole- 
cule, turning it into a free radi- 
cal and setting off a corrosive 
chain reaction. 

The process has been impli- 
cated in everything from cata- 
racts to cancer — and research- 
ers suspect it is what makes 
LDL, the bad form of cholester- 
ol, so dangerous. Steinberg and 
others have shown that when 
LDL lodges in arterial walls 
and becomes oxidized, it not 
only damages nearby tissues 
but attracts white blood cells. 
The white cells gorge them- 




selves on oxidized LDL and ac- 
cumulate within the arterial 
lining, causing plaques that 
narrow the arteries (chart). 
The resulting loss of blood flow 
can cause everything from 
chest pain to heart attacks. 

There are plenty of reasons 
for thinking that vitamin E, a 
natural antioxidant, could in- 
terfere with this process. Be- 
cause it mops up the unpaired 

electrons on free radicals, vita- 

mvko m j n g can keep LDL from oxi- 
dizing in a test tube. Experiments have 
shown that high doses can prevent heart 
disease in rabbits and monkeys, even when 
their cholesterol levels are astronomical. 
And though the evidence has been sketchy, 
human studies have hinted that the 100- to 
600-unit doses available in supplements 
might offer greater benefits than the tiny 
doses contained in various foods. 

Last week's findings were the strongest 
yet. In the larger of the two studies — both 
carried out at the Harvard School of Public 
Health and Brigham and Women's Hospi- 
tal — a team led by Dr. Meir Stampfer fol- 
lowed 87,000 female nurses from 1980 to 
1988. The women, all participants in a 
wide-ranging health survey begun in 1976, 
periodically filled out detailed question- 



Derailing a Deadly Disease 

Researchers suspect that heart disease begins when LDL 
cholesterol undergoes oxidation (the process that causes 
rust). Vitamin E may block that process. 



1. Low-density lipoproteins! LDLs i 
accumulate within arterial wall and 
become oxidized 



2. Oxidized LDLs, which 
can damage arterial 
tissue, attract white 
cells 




Oxidized 
LDL 



3. The white blood cells become 
engorged with oxidized LDLs and 
accumulate within arterial walls, 
eventually narrowing the artery 

kiihh NKWHWKKK 



naires about their diets, lifestyles and med- 
ical conditions. Analysis showed that when 
women took vitamin E supplements for at 
least two years (pushing their daily intake 
to at least 100 international units), they 
suffered 41 percent less heart disease than 
expected. Age, smoking and other risk fac- 
tors didn't account for the difference. The 
second study was based on a similar sur- 
vey of 40,000 male health professionals. In 
following the men from 1986 to 1990, epi- 
demiologist Eric Rimm and his colleagues 
found that those receiving daily vitamin E 
supplements of at least 100 units for two 
years reduced their risk of heart disease 
by 37 percent. 

Brisk sales: The new findings are sure to 
bolstersupplementsales. As it is, American 
consumersare popping vitamin Eas though 
their lives depended on it. Sales of the sup- 
plement reached $392 million in the United 
States last year — up from $260 million in 
1990 — and few cardiologists actively con- 
demn the trend. " There's growing evidence 
that antioxidants are effective in prevent- 
ing atherosclerosis," says Dr. John LaRosa, 
a lipid specialist at George Washington 
University and an American Heart Associ- 
ation designated spokesman on the issue. 
"All the studies point in the same direc- 
tion. It's very exciting because things like 
vitamin E are not all that expensive com- 
pared to the drugs that are used to treat 
cholesterol." Indeed, a month's supply of 
high-dose capsules can be had for 99 cents 
in a discount health store. 

Despite the mounting evidence, no one is 
calling vitamin E a proven lifesaver. Some 
experts worry that high doses could have 
unexpected long-term side effects (studies 
of up to six months haven't documented 
any). And even the most enthusiastic scien- 
tists agree that before they ad- 
^™^^~ viseeveryonetoconsumelOOor 
more units a day — a dose that is 
eight times the current Recom- 
mended Dietary Allowance — 
the benefits must be demon- 
strated in controlled clinical 
trials. Rather than simply re- 
porting their own habits, sub- 
jects in a clinical trial would 
receive either a placebo or a 
specified dose of vitamin E ev- 
ery day, and theeffects would be 
carefully measured. Several 
such studies are now in the 
works. But health-conscious 
scientists aren't waiting idly for 
the results to come in. "I eat 
carefully and exercise," says 
Rimm, the researcher who 
headed the men's study. "And 
for good measure, I take 200 
units of vitamin E every day." 

Geoffrey Cowley 

with Mary Hager 

and Karen Springen 



NEWSWEEK MAY 31, 1993 



C 1993 NEWSWEEK. INC 444 MADISON AVENUE, 
NEW YORK, N Y 1O022 ALL RIGHTS RESERVED 



147 



American Medical Association 

Physicians dedicated lo the health of America 




News Release 



EMBARGOED FOR RELEASE: 3 p.m. (CST) TUESDAY, MARCH 9, 1993 

For further information, contact: Paul Tarini, 312/464-5945 

COMMON FOLIC ACID DOSAGE MAY PREVENT 
NEURAL TUBE DEFECTS IN INFANTS 

CHICAGO--Dai 1 y use of the average over-the-counter multivitamin containing ton. 
acid may help women prevent their babies from being Dorn with neural tube 
defects ( NTDs ) , ^ike spina bifida, according to a study puDiisnea in this weeK ' ; 
Journal of the American Medical Association . 

"These findings suggest that daily per iconceptual intake of 0.4 mg (milligrams I 
of folic acid (the dose most commonly contained in over-the-counter multivitamin 
preparations) reduces the risk of occurrent NTDs by approximately 60 percent," 
writes Martha M. Werler, ScD, from the Slone Epidemiology Unit, Boston 
University School of Medicine, Brookline, Mass., with colleagues. 

Previous research has shown that women witli one child born with an NTD who take 
4-mg supplements of folic acid significantly reduce their risk of NTDs in then 
rater children, the authors say. The current study examined -mether folic acu 
supplements could prevent a first occurrence. 

From 1988 to 1991, the authors looked at births in tertiary ana birth hospitals 
in Boston, Philadelphia and Toronto. They report on mothers of 436 occurrent 
cases or NTD and motners of 2,615 children born with other major malformations. 
NTDs were defined as spina bifida, anencephaly or encephaloceie ; other 
malformations included chromosomal anomalies, ventricular septal defects, renai 
defects, transposition of great vessels, and limb reduction defects. 



leff Mnlter. Director 
Department of Science News 
Paul Tanni. Associate Science 
News Editor 



515 North State Street 
Chicago. Illinois WWII) 



112 4«4 5374 
!I2 4o4 5839 Fax 



148 



(FOLIC ACID) 

Pei i conceptual was 28 days before to 28 days after last menstrual period. 
Multivitamin use was daily with folic acid, less than daily with folic acia, 
daily ^ith folic acid unknown, and daily without folic acid. Folic acid was 
also broken out Dy dose. The mothers of 17 percent of the cases and 3 percent 
^r ir.e controls reported knowing of the folic acid-NTD hypothesis and were 
exciuaeo from further analysis. 

"We oLserved a statistically significant 60 percent reduction in the risk or 
occurrent NTDs among women who used daily vitamin supplements containing folic 
acid aria who were unaware of the folic acid-NTD hypothesis," they write. 

"Our data also provide the first direct evidence of a statistically significant 
reduction in occurrent NTD risk for supplements containing 0.4 nig of folic acid, 
the dose in most over-the-counter multivitamin preparations." 

They add that for dietary folate, there was a dose-related reduction in risK 
according to consumption. 

In an editorial accompanying the study, Godfrey P. Oakley, Jr, MD, MSPM, of the 
National Center for Environmental Health, Centers for Disease Control and 
Prevention, Atlanta, Ga., writes, "One of the most exciting medical findings i 
the last part of the 20th century is that folic acid, a simple, widely 
available, water-soluable vitamin, can prevent spina bifida and anencephai . 
(SBA) . " 

Uakie, notes that not all SBA is preventable by folic acid supplementation. 

he writes: "!E]ven though the rates of SBA in this country have falien 
considerably in the last 50 years, the proportion of SBA that could be prevented 
by folic acid supplementation remains significant . . . The most effective and 
cheapest way to prevent folic-acid preventable SBA is probably by fortifying a 
food staple with folic acid." 



149 



(FOLIC ACID) 

Oakley says besides available multivitamin supplements, women can get folic acu 
from certain fortified breakfast cereals or from foods rich in folates, such as 
Leafy, nark-green vegetables. 

"Wt :. ,w have the scientific basis to prevent folic-acid preventable SBA, nut 

only in the united States, but also in areas such as Mexico and Northern China 

where current rates are similar to [rates in some U.S. areas I in the 1930s," Lie 
says . 

(MEDIA ADVISORY: Author Martha M. Verier, ScD, from the Boston University School 
of Medicine, Brookline, Mass., can be reached through 617/638-8491; Godfrey P. 
Oakley, Jr, MD, MSPM, from the CDC, Atlanta, Ga . , can be reached through 
404/639-3286. ) 

» 



150 




WDZ 



<*> 



liliiiriifriiilil^iiiMIiffiliilisFiliiis 



*llllli r ili 




151 




FOR RESPONSE 



Vitamin Issues 

A regular update on the rationale for supplement 
legislation from the Council for Responsible Nutrition. 



NUTRITIONAL PROFILE OF AMERICANS 
CONGRESSIONAL BACKGROUNDER 

• Not meeting the Recommended Dietary Allowances (RDA) 

Many health professionals argue that healthy Americans can get enough nutrients from diet 
alone. However, most Americans are not meeting the Recommended Dietary Allowances for 
vitamins and minerals from diet alone. Most of these people fall into at least one risk group. 

Analysis of the U.S. Department of Agriculture's 1977-78 National Food Consumption Survey 
of 21,500 people revealed that only 3 percent consumed the recommended number of servings 
from the four food groups on each of the three days of the survey. Not a single person met all 
10 of the RDAs for vitamins A, B-6, B-12 and C, or for magnesium, calcium, iron, thiamin, 
riboflavin and protein In the most recent USDA nationwide survey in 1988, nutrient intakes did 
not change much from the previous survey. More than 70 percent of men and 80 percent of 
women failed to get even two-thirds of the RDA for one or more nutrients. 

Populations at Nutritional Risk 

• Senior Citizens 

Senior citizens often fail to achieve adequate nutrient intake because they do not metabolize vital 
nutrients as well as younger people and they often have limited appetites. Also, seniors are 
heavy users of medications, many of which impair nutritional status. A national survey 
(NHANES II) showed that 25 percent of seniors failed to get even two-thirds of the RDA for 
vitamin A, vitamin C, iron or calcium. 

• Pregnant Women 

Pregnant women have particularly high nutrient intake needs that are difficult to meet through 
diet alone. Inadequate nutrient intake has a negative impact on the outcome of pregnancy and 
the development of the infant. 

In 1992, the U.S. Public Health Service and health authorities in Britain both recommended that 
all women who are capable of becoming pregnant should be sure to consume 0.4 mg of folic acid 
(a B vitamin) daily in order to help prevent a class of birth defects called neural tube defects. 
The evidence shows that getting this amount of folic acid daily for several months before and 
after conception can reduce the incidence of neural tube defects by 60 to 80 percent. 



An association of the nutritional supplements, ingredients, and other nutritional products industry. 

1300 19th Street. NW • Suite 310 ♦ Washington. DC ♦ 20036-1609 ♦ (202) 872-1488 ♦ fax (202) 872-9594 



152 



• Infants 



Infants with inadequate intakes of iron are at risk of impaired mental and behavioral 
development. Studies have associated iron deficiency with lower mental development test scores 
in infants. In some studies, iron supplementation has produced rapid improvement. 

• Children 

Children from low-income families and even healthy young high school and college students 
often fail to meet nutrient needs from diet alone. Sibling studies reveal that those with better 
nutrient intakes in the first year of life have significantly higher IQs, better grades and fewer 
behavioral problems. 

• Dieters 

Dieters are also at risk. A study of eleven popular weight reducing programs found that the 
diets failed to provide adequate levels of calcium, iron, zinc, thiamin, vitamin B-6 and vitamin 
B-12. The popular trend towards reduced fat diets makes people particularly vulnerable to low 
vitamin E intakes. 

• Smokers 

Smokers have been found to have decreased levels of vitamins C and E. Studies show that 
smokers need to consume higher amounts of these vitamins to meet the serum levels of 
nonsmokers who are consuming RDA levels. France, Canada, New Zealand and the United 
States officially recommend that smokers increase their intake of vitamin C and have set the 
daily recommendations of vitamin C for smokers at a higher level than for nonsmokers. 

• Supplements Can Fill the Gap 

Poor dietary habits are the norm, not the exception. Vitamin and mineral supplements are a safe 
and effective means of improving nutrient intake to meet nutritional goals. For pennies a day: 

• Women can prevent some birth defects and improve pregnancy outcome. 

• Children can have better mental development and fewer behavioral problems. 

• Young adults can avoid anemia from inadequate iron intakes and can increase 
bone mass by consuming more calcium. 

• Senior citizens, who are particularly susceptible to infectious diseases, can 
improve immune function by supplementing their diets with a multivitamin 
product. 

• All Americans can help reduce the risk of chronic diseases such as cancer, heart 
disease and osteoporosis. 

In sum, scientific evidence increasingly demonstrates that generous intakes of some vitamins 
could potentially reduce disease risk and, therefore, substantially reduce health care costs. 



153 



APRIL 6, 1992 NOT FOR RESALE 




*1 992 Tiw Inc. Reprinted by permiS5*in. 



154 



Health 



COVER STORY 



The New Scoop 
On Vitamins 



They may be much more important than doctors thought in warding off 
cancer, heart disease and the ravages of aging — and, no, you may not 
be getting enough of these crucial nutrients in your diet 



By ANASTASIA TOUFEXIS 



It's raining. Flooding, to be precise. 
But business is as brisk as ever at 
Mrs. Gooch's natural-foods market 
in West Los Angeles. As usual, traf- 
fic is backed up along Palms Boule- 
vard as drivers wait for a spot in the store's 
parking lot. Inside, crowds jam the supple- 
ment section, which gleams with row upon 
row of small, white-capped vials. Here the 
true believers in the gospel of vitamins lin- 
ger over labels, comparing brand names 
and dosages, trading health sermons and 
nutritional arcana. They discuss the rela- 
tive merits of Buffered C and Lysine, as 
opposed to Bio-C Plus Rose Hips, or per- 
haps Bio-Absorbate Vitamin C Complex 
capsules. There are no fewer than 10 types 
and dosages of vitamin C to choose from, 
not to mention eight of vitamin E. 

Maryanne Latimer is among the faith- 
ful. A middle-age massage therapist, she 
has been plagued by chronic fatigue syn- 
drome and has therefore expanded her 
usual menu of vitamins and minerals. She 
shops at Mrs. Gooch's about once a week, 
in addition to other vitamin shops. "I take 
tons of vitamin C and E," she admits, plus 
calcium and a daily vitamin-mineral com- 
plex. Recently she added to her regimen 
three tablets a day of pantothenic acid (a 
lesser-known vitamin) "to help me wake 
up." Basically, says Latimer, "I'm looking 
for anything to make mc feel better. " 

But for every true believer in the pow- 
er of vitamins — and the U.S. has more 
devotees than any other country — there is 
an agnostic, a skeptic wh insists that vita- 
mins arc the opiate of the people. Among 



the doubters are many doctors. They have 
been persuaded by decades of public- 
health pronouncements, endorsed by the 
U.S. National Academy of Sciences and 
the National Institutes of Health, that 
claim people can get every nutrient they 
need from the food they eat. Popping vita- 
mins "doesn't do you any good," sniffs 
Dr. Victor Herbert, a professor of medi- 
cine at New.York City's Mount Sinai med- 
ical school. "We get all the vitamins we 
need in our diets. Taking supplements just 
gives you expensive urine." 

Wavering in confusion between these 
two schools of thought are the vast major- 
ity of Americans, wondering whom to be- 
lieve. They have heard the gospel of vita- 
min C as preached by the great chemist 
Linus Pauling, but they have also heard 
him ridiculed by health authorities. They 
may feed their children chewable vitamin 
tablets, but they question whether the pills 
are worth the high price. "I'd be thrilled to 
know what's right and to have someone 
tell me what to do," says Jane Traulsen, a 
mother of two who lives in White Plains, 
NY. "But all the information is so contra- 
dictory. It's like trying to make your way 
through a fog." 

But now, thanks to new research, the 
haze is beginning to lift. And it unveils a 
surprise: more and more scientists are 
starting to suspect that traditional medical 
views of vitamins and minerals have been 
too limited. While researchers may not 
endorse the expansive claims of hard-core 
vitamin enthusiasts, evidence suggests 
that the nutrients play a much more com 
plex role in assuring vitality and optimal 
health than was previously thought. Vita- 



mins — often in doses much higher than 
those usually recommended — may pro- 
tect against a host of ills ranging from 
birth defects and cataracts to heart dis- 
ease and cancer. Even more provocative 
are glimmerings that vitamins can stave 
off the normal ravages of aging. 

"The field is currently undergoing a 
paradigm shift," says Catherine Woteki, 
director of the food and nutrition board at 
the Institute of Medicine of the National 
Academy of Sciences. "We are now enter- 
ing the second wave of vitamin research," 
explains Jeffrey Blumberg, associate di- 
rector of the Human Nutrition Research 
Center on Aging at Tufts University. "The 
first wave was the discovery of vitamins 
and their role in combatting nutritional 
deficiencies such as rickets and beriberi. 
That occurred in the first half of the cen- 
tury. Now we're on the second wave. You 
don't need to take vitamin C to prevent 
scurvy in this country today. But you could 
need it for optimal health and the preven- 
tion of some chronic disease." 

Scientists have so far identified 13 or- 
ganic substances that are commonly la- 
beled vitamins. In the human body, they 
play a vital role in helping regulate the 
chemical reactions thai protect cells and 
convert food into energy and living tissue. 
Some vitamins are produced within the 
body. Vitamin D, for example, in manu- 
factured in the skin during exposure to 
sunlight, and three other vitamins (K. bio- 
tin and pantothenic acid) arc made inside 
the human gut by resident bacteria. But 
most vitamins must be ingested. 

Mystique ami faddish lore have long 
surrounded these essential biochemical 



IIMI AI'KII 6, I'"' 



155 




compounds. Consider vitamins C and E. 
"Somebody has made practically every 
claim you could dream of about these vita- 
mins," points out John Hathcock, chief of 
the experimental-nutrition branch of the 
Food and Drug Administration. People 
have been gobbling vitamin C for 20 years 
in the certainty that it can cure the com- 
mon cold, though evidence is still lacking. 
Vitamin E has been wildly popular for 
four decades because of its putative power 
to enhance sexual performance. In fact, 
studies indicate only that it is neces- 



sary for normal fertility in lab animals. 

More recently, B 6 has won favor as a 
relief for premenstrual syndrome. Vita- 
min A is touted as a rejuvenator by people 
who mistakenly believe that it. like its syn- 
thetic relative Retin-A, can give wrinkled, 
mottled skin that youthful rosy glow. "We 
never know what next year's fad is going to 
be," says Hathcock. 

It is just this whiff of quackery that 
made vitamins a research backwater for 
years. Most reputable scientists steered 
clear, viewing the field as fringe medicine 



awash with kooks and fanatics. A re- 
searcher who showed interest could lose 
respect and funding. Certainly Linus Paul- 
ing lost much of his Nobel-laureate luster 
when he began championing vitamin C 
back in 1970 as a panacea for everything 
from the common cold to cancer. Drug 
companies too have been leery of commit- 
ting substantial energy and money to stud- 
ies, since the payoff is relatively small: vi- 
tamin chemical formulas are in the public 
domain and cannot be patented. 

But attitudes have been shifting over 



TIME, APRIL 6. 1992 



156 



Health 

CAN YOU SURVIVE BY 
PILLS ALONE? 

Call it the Jetson diet: a futuristic feast of 
prefab pellets containing all the nourish- 
ment any 21st century citizen would want. 
It makes for a nice cartoon fantasy, but 
could people really eat this way? Not a 
chance. Real food is here to stay. 

Multiple-vitamin pills do not contain the 
fiber, carbohydrates and proteins neces- 
sary for maintaining the body and giving it 
energy. Such nutrients can be put into pills, 
but they would have to be taken in such 
large quantities that they would be an im- 
practical — not to mention tasteless — sub- 
stitute for real food. 

Food also contains a myriad of obscure 
nutrients, such as phenols, flavones and lutein, that scientists cannot yet fully understand, 
much less put into a safe, effective pill form. And many vital nutrients have undoubtedly not 
been identified at all. But even if a full-service nutrient pill were formulated, it probably 
could not satisfy some basic human desires: hunger and the joy of savoring good food. 




the past few decades. Despite all the 
sneering, Pauling's speculations did get 
more scientists thinking about vitamins' 
impressive powers. As a class of com- 
pounds, they are known to produce huge- 
ly dramatic effects when missing from the 
diet: scurvy, pernicious anemia, rickets. 
What other exciting properties might 
they — or related compounds — have? 

Another driving force in the U.S. is the 
new "demographic imperative." With a 
rapidly aging population, America has 
moved its medical focus from treating 
acute illness to caring for chronic mala- 
dies like heart disease and cancer — a shift 
that has sent health-care costs skyward. 
"There's a growing appreciation of the 
need to find the most economical way to 
treat and prevent chronic disease," notes 
Dr. Charles Butterworth Jr. of the Uni- 



versity of Alabama. "Food and vitamins 
are not that expensive." Calculates Tufts' 
Blumberg: "We could save billions of dol- 
lars if we could delay the onset of chronic 
diseases by as little as 10 years." 

Overriding all else, however, is the 
impact of scientific studies. Beginning in 
the 1970s, population surveys worldwide 
started to uncover a consistent link be- 
tween diet and health. A diet rich in fruits 
and vegetables, for instance, became asso- 
ciated with a lowered incidence of cancer 
and heart disease. Researchers then 
turned to examining the data nutrient by 
nutrient, looking at minerals as well as vi- 
tamins, to see which are tied most closely 
with specific ailments. Low vitamin C in- 
take appears to be associated with a high- 
er risk of cancer, low levels of folic 
acid with a greater chance of birth defects, 




ARE PILLS AS GOOD A 
SOURCE AS FOOD? 

<> A pill cannot deliver the same range of 
nutrients as food, but what if you want a 
megadose of a particular vitamin? Will a 
supplement do the trick, or would it be 
better to eat bushels of broccoli? In 
theory, pills can provide dependable 
doses of genuine vitamins and minerals. 
"Vitamin C is a molecule, whether nature 
synthesizes it or man does," observes 
Gladys Block, a nutrition professor at 
the University of California, Berkeley. 
But that assumes the pill is properly 
made — which is not always true. In 1 989, for instance, a study found that more than half of 
calcium carbonate supplements on the U.S. market could not be easily digested. Pills with 
thick coatings are suspect, while gel caps present the fewest problems. If well made, 
however, a pill Is no worse than a vegetable at delivering selected nutrients to the body, and 
may work better for those who refuse to eat their greens. 



and high calcium consumption 
with a decreased danger of 
osteoporosis. 

Intrigued by such clues, the 
National Institutes of Health, 
universities and other research 
organizations began funding lab- 
oratory and clinical investiga- 
tions. By the late '80s, research 
exploring vitamins' potential in 
protecting against disease was on 
its way to respectability. Though 
the evidence is still preliminary, 
scientists are excited about sever- 
al nutrients. 

One vitamin attracting atten- 
tion is folic acid, also known as 
folate, which was first isolated 
from spinach. This B vitamin ap- 
pears to guard against two of the 
most common and devastating 
neurological defects afflicting 
newborns in the U.S.: spina bi- 
fida, in which there is incom- 
plete closure of the spine, and 
anencephaly, in which the brain fails to 
develop fully. British researchers found 
that when women who had already given 
birth to a malformed child received folic 
acid supplements during a subsequent 
pregnancy, the chances of a second tragic 
birth fell sharply. 

Another enticing finding reported last 
January established a link between folic 
acid and prevention of cervical cancer. 
According to a study at the University of 
Alabama's medical school, women who 
have been exposed to a virus that causes 
this cancer are five times as likely to devel- 
op precancerous lesions if they have low 
blood levels of folic acid. The discovery 
may help explain why cervical cancer is 
more common among the poor. Indigent 
women usually eat few vegetables and 
fruits, which are prime sources of folate. 
Says Butterworth, head of the re- 
search team: "It looks like many 
cases of cervical dysplasia |a pre- 
cancerous condition] could be 
prevented with a healthy diet." 

Vitamin K. long known to 
promote blood clotting, appears 
to help bones retain calcium. 
Rapid calcium loss is a major 
plague among postmenopausal 
women, giving rise to the fragile- 
bones syndrome called osteopo- 
rosis. A recent Dutch study of 
1,500 women ages 45 to 80 
found that calcium loss (as mea- 
sured in urine samples) could be 
halved with daily supplements of 
vitamin K. 

Most of the excitement, how- 
ever, is being generated by a 
group of vitamins — C. F. and beta 
carotene, the chemical parent of 
vitamin A — that are known as 



Illustrations lor TIME by Gary Zamchick 



157 



/BETA Be Bi 

! CAROTENE 



A: liver, egg yolhs, 
whole milk, butter 

BETA CAROTENE": 
dark green leaf) 
vegetables, yellow 
and orange 
vegetables and 
fruits 



Meats, 

poultry, 

fish, 

fruits, 

nuts, 

vegetables 



Meats, milk 
products, eggs, 
liver, fish 



Citrus fruit, Liver, butter, Nuts, seeds, 

green peppers, fatty fish, egg whole grains, 

strawberries, yolks, fortified vegetable and 

raw cabbage, milk. Also fish-liver oils 
green leafy produced when 
vegetables skin is 

exposed to ^X 

sunlieht. TSi 



Green leafy 
vegetables, 
liver 



vegetables, meats, 



Established Prevents night 
benefit blindness and 
xerophthalmia (a 
common cause of 
blindness among 
children in poor 
countries) 



Helps prevent Prevents 
pernicious anemia scurvy, loose 
I teeth; fights 

hemorrhage 



Prevents; Helps prevent 
rickets (bone retrolental 
malformation} fibroplasia (an 
_ eye disorder in 
premature 



Helps protect Helps 



al against 

ia (an cervical 

derin dysplasia 

(precancerous 

anemia changes in 
I cells of the 
| uterine cervix) , 



antioxidants. These nutrients appear to be 
able to defuse the volatile toxic molecules, 
known as oxygen-free radicals, that are a 
byproduct of norma] metabolism in cells. 
These molecules are also created in the 
body by exposure to sunlight. X rays, 
ozone, tobacco smoke, car exhaust and 
other environmental pollutants. 

Free radicals are cellular renegades; 
they wreak havoc by damaging dna, alter- 
ing biochemical compounds, corroding 
cell membranes and killing cells outright. 
Such molecular mayhem, scientists in- 
creasingly believe, plays a major role in 
the development of ailments like cancer, 
heart or lung disease and cataracts. Many 
researchers are convinced that the cumu- 
lative effects of free radicals also under- 
lie the gradual deterioration that is 
the hallmark of aging in all individuals, 
healthy as well as sick. Antioxidants, stud- 
ies suggest, might help stem the damage 
by neutralizing free radicals. In effect they 
perform as cellular sheriffs, collaring the 
radicals and hauling them away. 

Supporters of this theory speculate 
that antioxidants may one day revolution- 
ize health care. Biochemist William Pryor, 



director of the Biodynamics Institute at 
Louisiana State University, foresees 
screening people through a simple urine, 
blood or breath test to assess how much 
damage free radicals have done to tissue, 
much as patients today are screened for 
high cholesterol. "If you can predict who 
is most susceptible to oxidative stress," 
notes Pryor, "you can treat them with 
antioxidants more effectively." Ultimate- 
ly, says biochemist Bruce Ames at the 
University of California, Berkeley, "we're 
going to be able to get people to live a lot 
longer than anyone thinks." 

In that brave new world, people might 
pop vitamins C and E to deter the devel- 
opment of cataracts, the clouding of the 
lens in the eye that afflicts 20% of Ameri- 
cans over 65. Patients taking high doses of 
both vitamins appear to reduce the risk of 
cataracts by at least 50%, according to a 
Canadian study. Vitamin C may be es- 
pecially efficient because it concentrates 
in the eye. Scientists at the National Eye 
Institute estimate that if cataract devel- 
opment could be delayed by 10 years, 
about half of cataract surgery could be 
eliminated. 



Vitamin E may be particularly helpful 
in preventing free radicals from injuring 
the heart. Doctors speculate that giving 
the vitamin to patients during or shortly 
after a heart attack might help preserve 
heart muscle. One clue from a study at 
Toronto General Hospital: rabbits inject- 
ed with vitamin E within two hours of a 
heart attack showed 78% less damage to 
heart tissue than was expected. The vita- 
min appears to speed recovery in patients 
who have had coronary-bypass opera- 
tions, suggesting that nutrient supple- 
ments may one day become part of stan- 
dard pre-op procedure. 

Chugging vitamin E seems to boost 
the immune system in healthy old people, 
raising the possibility that supplements 
could help thwart life-threatening infec- 
tions. The nutrient may also turn out to be 
a potent lung saver, warding off the depre- 
dations of cigarette smoke, car exhaust 
and other pollutants. "The effects of air 
pollution are chronic," says Dr. Daniel 
Menzel of the University of California at 
Irvine. "Over a lifetime people develop 
serious diseases like bronchitis and em- 
physema. We have fed animals in our labs 



TIME. APRIL6, 1992 



158 



Health 



DO OLDER PEOPLE HAVE DIFFERENT 
VITAMIN NEEDS? 

Don't assume Grandma and Grandpa can get by on fewer 
nutrients just because they are not as active as they once 
were. That widely held belief is being challenged by new 
research suggesting that the elderly need even more of some 
vitamins than the young. A Tufts University study indicated 
that people over 60 may need about a third more vitamin B 6 
than young adults do to maintain good nutrition. Vitamin D 
consumption apparently should increase with age as well. 

The elderly may not be able to process and synthesize vital 
nutrients as efficiently as younger people. Moreover, 
medications commonly prescribed for seniors, such as anti- 
inflammatory agents or diuretics, can hinder vitamin 
absorption. And because powers of taste diminish with age, 
old folks sometimes have flagging appetites and thus are in 
danger of not getting enough vitamins from their diets. 




vitamin E and have found that they have 
fewer lung lesions and that they live long- 
er." Menzel suggests that priming chil- 
dren with doses of antioxidants could pro- 
tect them against lung disease as adults, 
much the way fluoridated water protects 
them against tooth decay. 

For patients found to have Parkinson's 
disease, vitamin E may hold special prom- 
ise. The nutrient seems to delay the ap- 
pearance of tremors, rigidity and loss of 
balance, thus postponing the need for 
therapy with dopamine. The vitamin also 
appears to alleviate some of the unpleas- 
ant side effects of antipsychotic drugs, 
such as twitchy hands, face and feet. 

Holding center stage in antioxidant 
circles, however, is beta carotene, a com- 
plex deep orange compound that is natu- 
rally abundant in sweet potatoes, carrots 
and cantaloupes. Beta carotene is turned 
into vitamin A by the body as needed. 
That makes it impossible to overdose on 
beta carotene, even though taking too 




much vitamin A can lead to liver damage 
and other effects. 

Doctors at Harvard Medical School, 
who have been following 22,000 male phy- 
sicians as part of a 10-year health study, 
have made a stunning discovery about 
beta carotene. They found that men with a 
history of cardiac disease who were given 
beta carotene supplements of 5C mg every 
other day suffered half as many heart 
attacks, strokes and deaths as those pop- 
ping placebo pills. No heart attacks oc- 
curred among those in this group who re- 
ceived aspirin along with the beta caro- 
tene capsules. The Harvard researchers 
have begun a trial in 45,000 postmeno- 
pausal women to see if a similar effect oc- 
curs in women. Scientists speculate that 
the antioxidant helps prevent those nasty 
oxygen-free radicals from transforming 
ldl, the bad form of cholesterol, into an 
even more menacing artery dogger. 

Beta carotene may prove powerful in 
combatting cancer as well. In countries 



DOES IT MATTER WHICH BRAND 
YOU BUY? 

Buying vitamins can be a befuddling experience. Even if 
you can figure out the best formulation (with zinc or 
without?), quantity and dose, you probably don't know 
what to make of other scientific-sounding claims like 
"proven release" or "high absorbency." Pricing too can 
seem as arbitrary as the color of the pill. 

Most advertising claims are just hype, but studies 
conducted in the U.S. several years ago showed 
significant brand differences in such characteristics as 
how fast a pill will dissolve in the body. Unfortunately, 
those surveys are out of date. "For now, we have to buy 
our vitamins on faith," concedes Dr. Ralph Shangraw, a 
leading expert on food supplements at the University of 
Maryland. While U.S. officials intend to set up stricter 
standards for vitamins next year, few other countries 
have similar controls. Shoppers would do well to stick 
to brands sold by reputable stores and keep in mind that 
the highest priced pill is not necessarily the best. 



such as Japan and Norway, where diets 
are rich in beta carotene, the populations 
have a low incidence of lung, colon, pros- 
tate, cervical and breast cancer. And a 
study at the University of Arizona Cancer 
Center found that three to six months of 
daily beta carotene pills dramatically re- 
duced precancerous mouth lesions in 70% 
of patients. Pharmaceutical giant Hoff- 
mann-La Roche is so enamored with beta 
carotene that it plans to open a Freeport, 
Texas, plant next year that will churn out 
350 tons of the nutrient annually, or 
enough to supply a daily 6 mg capsule to 
virtually every American adult. 

As vitamin research surges, confusion 
swirls around two basic questions: How 
much of these nutrients is needed, and 
what's the best way to get them — in food 
or in supplements? For half a century, 
Americans' vitamin intake has been guid- 
ed by the Recommended Daily Allow- 
ances, or rdas. Introduced during World 
War II as a way to ensure that military re- 
cruits did not suffer from 
malnutrition, the levels 
quickly became a standard 
for the general population. 
Technically the National 
Academy of Sciences sets 
different rdas for people 
of different ages and sexes, 
but to simplify matters, the 
fda has since 1968 taken 
the highest rdas — those 
appropriate for teenage 
boys — and endorsed them 
as the national standard. 
These are the numbers 
that appear on cereal 
boxes. 

Two years ago, the fda 
announced plans to change 
this policy. Instead of en- 
dorsing an allotment ap- 
propriate to ravenous, last- 
growing teenage males, it 
would simply average the 



TIMl.AI'RU (.. 1W2 



159 



CAN YOU OVERDOSE? 

Too much of a good thing can have unex- 
pected consequences. Just ask people who 
have gulped gallons of carrot juice, which is 
rich in beta carotene, only to find that the 
palms of their hands and the soles of their 
feet turned a dull yellowy orange. 

The carrot-juice syndrome is generally 
thought to be harmless and reversible, but 
overdosing on some other vitamins and 
minerals can have serious side effects: 

Vitamin A: Gorging on this compound in 
doses of more than 25,000 lUs (five times 
the RDA) can lead to liver damage, hair loss, 
blurred vision and headaches. 



Vitamin B e : Ingesting more than 400 mg a 
day (200 times the RD/v) can cause numb- 
ness in the mouth and hands and difficulty in walking. 

Vitamin C: It was once believed to cause kidney stones, but 
experts now say there is no solid evidence of dangerous side 




effects from vitamin C. High doses can pro- 
duce stomachaches and diarrhea. 

Vitamin D: In daily doses of 50,000 lUs 
(125 times the U.S. RDA), the sunshine vi- 
tamin can cause the buildup of calcium de- 
posits that can interfere with the function- 
ing of muscles, including heart tissue. 
While sunbathing will never create an over- 
dose, taking too many supplements can. 

Niacin: Doctors prescribe doses of 2,000 
mg (100 times the RDA) to help lower cho- 
lesterol. But patients who take that much 
should be monitored for possible symp- 
toms of jaundice and liver damage. 



Iron: Those who want to bolster their red- 
blood-cell count, especially elderly people 
and menstruating women, have been taking iron supplements 
for years. Daily doses higher than 100 mg (six times the RDA) 
could interfere with absorption of zinc, a mineral that speeds 
wound healing and helps regulate the immune system. 



rdas for different age groups. The new fig- 
ures are considerably lower and, says the 
agency, are a better barometer of the typi- 
cal American 's nutritional needs. Essential- 
ly they reflect the requirements of adult 
women. The agency has proposed slashing 
the rdas for many vitamins, including A, B, 
C and E, as well as nutrients such as iron, by 
10% to 80%. The rda would also acquire a 
new name: the Reference Daily Intake, or 
rdi. (On food labels the rdi would be listed 
as the Daily Value, or DV.) "By using the 
old rdas, you're trying to make the entire 
population consume more nutrients than it 
needs," explains John Vanderveen, direc- 
tor of the fda's nutrition division. "Young 
males need more nutrients than women, 
children and the elderly." 

But the move to slash rdas, scheduled 
to go into effect next year, flies in the face 
of research that suggests benefits from 
higher doses of vitamins. The current rda 
for vitamin C, for example, is 60 mg. But 
to get a protective effect against cataracts 
or cancer may require as much as 100 mg. 
Similarly, vitamin E may need a boost 
from the rda of 10 mg to 100 mg. (There 
is no rda for beta carotene, but scientists 
speculate that 25 mg or more a day could 
be needed.) 

Already many people consider the 
old rdas, with their focus on preventing 
scurvy and other rare deficiency prob- 
lems, to be irrelevant to real health 
needs. "Our clientele generally thinks of 
the rda as a kind of joke," says Sandy 
Gooch, owner of the chain of seven Mrs. 
Gooch's markets in Southern California. 
What's actually needed, vitamin advo- 
cates suggest, is guidelines for optimal 
consumption. That amount may very 
well depend upon age, sex and life-style 
habits. 

Do people have to take supplements 



to get enough vitamins? Nutritionists and 
doctors agree that everyone's basic needs 
could be met by eating a diet rich in vege- 
tables and fruits. The U.S. government's 
1990 dietary guidelines urge an ambitious- 
ly varied meal plan: three to five servings 
daily of vegetables, two to four of fruit, as 
well as six to 1 1 of breads, rice, pasta and 
grains and two to three of meat, eggs, 
poultry and dried beans. 

As far as America is con- 
cerned, most people don't 
even come close. A mere 9% 
of adults manage to consume 
five servings of fruits and veg- 
etables each day, according to the Nation- 
al Center for Health Statistics. By and 
large. Americans simply don't like vegeta- 
bles. The most prominent example: Presi- 
dent Bush, who once admitted he detest- 
ed broccoli, now has taken to deriding 
carrots as "orange broccoli." 

Nonetheless, failing to match daily di- 
etary guidelines is no reason to go running 
for the vitamin bottle. "What you do one 
day or one week isn't the whole story," 
stresses Jeanne Goldberg, assistant pro- 
fessor of nutrition at Tufts. "It's what your 
general eating patterns are." Blitzing on 
junk food for a day or two is no problem if 
over the long haul a diet regularly con- 
tains fruits and veggies. If it does not, pop- 
ping pills is a good insurance policy, espe- 
cially important for those who reject 
greens outright. Supplements are also 
useful to people with special conditions, 
including shut-ins, alcoholics and those on 
very restrictive diets, who tend to be poor- 
ly nourished. 

Virtually all experts agree that a dai- 
ly multivitamin won't hurt anybody. 
Opinion is divided, however, about 
whether people should be taking high 



doses of vitamins to prevent chronic dis- 
ease or delay aging. Some argue that 
enough evidence is in to justify taking 
moderately high amounts of antioxi- 
dants. Several researchers admit they are 
already doing so. 

Others believe it is too soon to be mak- 
ing recommendations to the public. The 
long-term effects of high-dose supple- 
ments are still unknown, and doctors warn 
of dangers even in the short term. Too 
much vitamin D, for example, can cause 
damaging calcium deposits in muscle tis- 
sue, including the heart. 

Last February the fda rejected as 
premature applications by vitamin mak- 
ers to promote folic acid as a means of 
preventing neural-tube birth defects, 
antioxidants as a hedge against cancer, 
and zinc as a booster of aging immune 
systems. Both federal and state regula- 
tory agencies have been cracking down 
on nutrient health claims. The fda says 
it will hold label claims to standards sim- 
ilar to those applied to drugs. Advises 
Dr. Walter Willett of the Harvard 
School of Public Health: "At this time I 
say don't take megadoses, but I'm not 
ruling out that in two or three years we 
might change our mind." 

The wisest strategy right now may be 
to redouble those efforts to eat more 
broccoli and carrots, spinach and squash. 
And to follow the familiar exhortations: 
get up and get moving, cut down fat and 
cut out smoking. No matter how powerful 
antioxidants and the other nutrients tum 
out to be, they will never be a substitute 
for salutary habits. But stay tuned. Vita- 
mins promise to continue to unfold as one 
of the great and hopeful health stories of 
our day. — Reported by Janice M. Horowitz/ 
New York, Elaine LattertylLos Angeles and Dick 
Thompson/Washington 



TIME. APRIL h.lTO 



160 

Mr. Towns. Ms. Whittekin. 

STATEMENT OF MARTIE WHITTEKIN, PRESIDENT, NATIONAL 
NUTRITIONAL FOODS ASSOCIATION 

Ms. Whittekin. Before I start my comments, I want to thank 
you, Mr. Chairman, for this opportunity today and also thank you 
and Mr. Schifif and others who have been cosponsors of Congress- 
man Richardson's bill. We appreciate that. 

While we are spending, as a country, over $3 billion per day on 
health care in America, the Food and Drug Administration is inap- 
propriately regulating food and perhaps even water as drugs or 
food additives. 

The FDA's excessively narrow bureaucratic attitude is costing 
taxpayers billions and harming many more thousands of Americans 
than it is allegedly protecting. That is the reason that Congress 
must act. 

Let me explain further. As Candidate Clinton, HHS Secretary 
Shalala, a host of doctors and health policy experts, and 100 mil- 
lion dietary supplement users have said, disease prevention 
through a healthy life style and through the informed use of die- 
tary supplements is far better than spending an everincreasing 
percentage of our GNP on disease treatment. 

In my testimony, and in a chart which I would like to call to your 
attention, are just a few of the very many areas of investigation 
into how many dollars could be saved by improved health practices 
and nutrition, also including supplementation. And this is just the 
tip of the iceberg. 

When it passed the Nutrition Labeling and Education Act, Con- 
gress clearly recognized the value to consumers of the benefits of 
good nutrition. The FDA was directed in a statute to review 10 
health claims. Congress did not tell the FDA to apply a drug or 
food additive standard to the review of these claims. All that was 
required was that there be significant scientific agreement. But 
something got lost in the translation as FDA has chosen to apply 
an almost insurmountable standard. Only one claim for dietary 
supplements has been approved. It is actually easier to get ap- 
proval for a drug. Mr. Chairman, this makes no sense. The Con- 
gress must stop the FDA, a regulatory agency with a rather narrow 
concern, from dictating broad public health policy. 

For example, sooner or later the FDA will approve a health claim 
for folic acid and neural tube birth defects, following the lead of 
other government agencies. But how many babies have been lost in 
the process? Approximately 1,250 just since the time that other 
agencies have come out in favor of making this connection known 
on labels. 

But the primary problem will remain; the FDA's head-in-the- 
sand attitude affects hundreds of other dietary substances. 

Let's talk a moment about safety because that is something that 
the FDA likes to bring up. I would call your attention to another 
chart which is also in the written materials, that helps us to get 
a handle on what they are talking about in the way of safety. 

And if you notice deaths from adverse drug reactions might be 
100,000 deaths per year. A number of other things that you can 
see, in descending order, show how relatively safe all of our dietary 



161 

supplement products are. One that is not on here is hair dryers, 
which account for 10 deaths per year. 

But the FDA doesn't seem to be paying attention to the fact that 
they are just a regulatory agency; that their mission is not about 
cost-benefit ratios and good health policy. That is the concern of 
Congress. The FDA's concern appears to be just making their job 
easy by saying "no," while at the same time protecting its backside 
from criticism. 

If the FDA approves a drug that saves lives, people say that they 
are doing their job. But if they approve a dietary supplement that 
costs one life, thev are criticized. The FDA has a strong institu- 
tional bias to say ' no." 

In the area of disease prevention from dietary supplements, this 
results in terrible public policy. The FDA, for example, considers 
herb tea a food additive because it is mixed with water. By its own 
admission, the FDA will continue to waste its scarce resources on 
this type of theoretical nonsense, unless the Congress instructs it 
to exclude dietary supplements. 

We are not an industry that is unregulated. We don't propose to 
be an industry that is unregulated. Indeed, we have asked for the 
FDA's input on many occasions, including before House bill 1709 
was introduced. I have to say that their input was not forthcoming. 

I was delighted to hear this morning that the FDA intends to 
seek out the views of other groups such as ours. That would be a 
welcome change from the past. And I would assume that that 
means that they will extend the deadline that they have put of Au- 
gust 18 for getting comments, because that is a pretty unreason- 
able deadline; from June 18, to August 18, in the middle of sum- 
mer, if they really want to hear from other people. 

Thank you. 

Mr. Towns. Thank you. 

[The prepared statement of Ms. Whittekin follows:] 



162 



Testimony 

Before the Subcommittee on Human Resources and 

Intergovernmental Relations of the 

Committee on Government Operations 



July 20, 1993 



Martie Whittekin 

President 

National Nutritional Foods Association 

150 East Paularino, Suite 285 

Costa Mesa, CA. 92626 



163 
TESTIMONY FOR JULY 20 HEARING 



Mr. Chairman and Members of the Subcommittee, thank you for the 
opportunity to testify. I ask that my prepared statement be inserted into the 
record in full and that I be allowed to present an oral summary. 

Mr. Chairman, your leadership on this important health care issue is 
very much appreciated. Oversight and legislative actions by the Congress are 
urgently needed to prevent the Food and Drug Administration from dealing 
a crippling blow to the dietary supplement industry and effectively denying 
health preservation information to millions of Americans-information that 
could save pain, anguish and billions of health care dollars. Let me explain. 

The FDA is a regulatory agency with a rather narrow focus. It is 
concerned with product approvals and safety. Its mission is not to formulate 
broad public health policy, a task which is the responsibility of the White 
House, the Department of HHS and, of course, the Congress. Nonetheless, 
the FDA's overzealous regulation of dietary supplements will unnecessarily 
delay, or even foreclose, promising health policy options in the area of 
prevention and wellness unless the Congress and the Administration become 
involved. 

The FDA has a 40 year record of hostility toward the dietary 
supplement industry. In the 1950's, the FDA wired its officers with bugging 
devices to record what retailers told consumers about supplements. In the 
1960's, the Agency refused to recognize the health benefits of zinc and 
Vitamin E, both now acknowledged as essential nutrients, and in the 1970's 
attempted to regulate Vitamins A and D as drugs. After the Rodgers- 
Proxmire Amendment of 1976 prohibited the FDA from establishing potency 
limits on vitamins and minerals, the Agency has attempted to regulate 
dietary supplements as food additives rather than as nutrients. Under this 
approach, the agency doesn't have to prove that the supplement is or may be 
unsafe. Once it prevails that the supplement contains an unapproved food 
additive, the burden is on the manufacturer or distributor of the supplement 
to prove to the satisfaction of the Agency or the court that the product is safe, 
often an impossible task. Two recent Federal court of appeals decisions have 
rejected the FDA's view that supplements are food additives rather than food, 
at least as far as single ingredient supplements are concerned. However, the 
Agency has clearly stated its intent to regulate supplements with multiple 
ingredients as food additives and to similarly treat single ingredient 
supplements in districts outside the jurisdiction of the two appellate courts. 



164 



This misinterpretation of the law could, in time, be reversed in the 
courts. However, in June, the Agency published an agenda of actions that 
raise new threats to the ability of Americans to obtain supplements and 
truthful information about their abilities to deter or prevent diseases. 

In the advance notice of proposed rulemaking on dietary supplements 
and the FDA's Task Force on Dietary Supplements Final Report, the Agency 
clearly signals its intent to regulate amino acids as drugs, to treat herbs and 
other dietary substances as food additives or drugs, and even to try another 
back door attempt to limit the potency of vitamins and minerals. Here I refer 
to the proposal to establish a daily "dietary supplement limit" and the even 
more onerous idea to require the industry to prove safety (through GRAS 
petitions) for any level above the Recommended Daily Allowance. What is 
totally lacking in this myopic view is any serious consideration of the benefits 
of supplements. 

In 1992, we spent about 900 billion dollars on health care in the United 
States and the figure is increasing at an alarming rate. This is why President 
Clinton has made health care reform a top priority and why you and your 
colleagues in the Congress are struggling to find an effective and affordable 
solution to this problem. It is generally acknowledged that disease 
prevention is far less costly than disease treatment. A large and growing 
volume of research by doctors and scientists at leading institutions across the 
country strongly suggests that dietary supplements can help preserve health. 
Studies related supplement use to delayed onset of a number of diseases 
including heart disease, cancers of the lung, breast, cervix, esophagus, oral 
cavity, stomach, bladder, pancreas and ovary, hip fracture, angina, neural 
tube defects, reduced cognitive functioning in the elderly population and 
retinitis pigmentosa (an inherited degenerative disease of the retina). Chart 1 
summarizes the potential savings in disease care costs from improved 
nutrition, including dietary supplements, and the improved dissemination of 
prevention information. The estimates from the three studies cited total over 
$200 billion. 

Thus, there is good evidence that the increased use of dietary 
supplements could save millions if not billions of dollars while significantly 
improving the lives of millions of Americans. And boy, do we need it. An 
April 1993 survey of doctors and nurses who specialize in treatment of the 
elderly found that over 25% of their patients suffer from malnutrition and the 
number rises to almost 50% for patients in hospitals or nursing homes. For 
the population as a whole, only about 9% of adults consume the 



165 



recommended five servings a day of fruits and vegetables, and only about 
24% are even somewhat aware of the USDA's food pyramid. Even worse, a 
1992 Louis Harris survey found that Americans exercise less, are fatter, sleep 
less, are more stressed and eat less wisely than they did in the early 1980's, 
when a similar survey was conducted. 

One would think that this exciting possibility would be one of the very 
highest priorities of the Government and would be pursued with dispatch. 
Unfortunately, the reverse is true, as the FDA's treatment of folic acid and 
other supplements shows. 

In the Nutrition Education and Labeling Act of 1990, the Congress 
directed that the FDA review 10 specific health claims for food and 
supplements, including folic acid in the prevention of birth defects, and the 
use of several anti-oxidants and the prevention of certain cancers. 
Notwithstanding a small mountain of evidence and supporting comments by 
prominent scientists across the country, the FDA rejected the idea that health 
preservation claims would be allowed for folic acid and the anti-oxidants. 
The rejection was contained in the FDA's proposed rule published in 
November 1991 and was unchanged in the January 1993 final rule. 

While the Government's regulatory hand was rejecting health claims 
for which there was overwhelming evidence, the Government's physicians 
were advising women to take folic acid to reduce the chance of spina bifida 
and other neural tube birth defects. In August 1991, the U.S. Centers for 
Disease Control and Prevention recommended that all women who had a 
pregnancy affected by neural tube defects take 4.0 mg of folic acid at least 1 
month before conception and during the first 3 months of pregnancy, and in 
September 1992, the Centers for Disease Control published a recommendation 
by the U.S. Public Health Service that all women of child bearing age should 
consume .4 mg of folic acid daily to reduce the incidence of neural tube 
defects. 

This bureaucratic double think would be humorous if it were not for 
the very real human tragedy involved. The CDC reports that about 2500 
infants are born each year with spina bifida and anencephaly, but that it is 
possible to reduce the number of cases by 50% through daily consumption of 
.4 mg of folic acid. Not only has the FDA rejected this health preservation 
claim, their labeling rules muzzle the dietary supplement industry so that it 
cannot communicate this U.S. Government information to our customers. If I 
put this publication by the CDC next to folic acid in my store and put up a 



166 



sign to alert women to the news, my product would be liable to seizure and I 
could be arrested. 

Most Americans do not read scientific journals or the weekly 
publication by the CDC. They get their information primarily from labeling 
and promotional materials. Thus, scientists and other highly educated 
elements of the population are the most likely to obtain~and benefit from— 
potentially life saving information about folic acid and other supplements 
while less educated and poorer Americans, and those with little time to read 
journals, are left to fend for themselves. Like many other doctors and 
scientists, Dr. Phillip Lee, the new Assistant Secretary of Health, takes 
Vitamin E. He certainly didn't get his information from the label or labeling. 

In fact, a recent government study suggests that the people who need 
health information the most are not getting it. The National Center for 
Health Statistics reported on July 7 that the health gap between wealthier and 
better educated Americans and their poorer and less educated counterparts 
was large and growing. In 1986, people with a family income of less than 
$9,000 per year had a death rate more than three times that of persons with 
family incomes of $25,000 or more. The study also found that among various 
income groups, the level of inequality in mortality rates more than doubled 
between 1960 and 1986. 

The study's author, Dr. Gregory Pappas, noted that people of higher 
socio-economic status may have longer lives because they live in healthier 
neighborhoods and have rapidly adopted healthier patterns of behavior 
including a low fat diet, exercise and the avoidance of smoking. 

These lifestyle changes did not happen by accident. They resulted 
from the effective communication of information about health, a good deal of 
which was disseminated by the government at taxpayer expense. But as we 
can see, this information is not getting through to the poorer and lesser 
educated segments of the population. Unfortunately, the FDA will not allow 
the supplement industry to communicate truthful and non-misleading 
information about the health benefits of most of its products on their labels or 
in their labeling. The result is that the tremendous marketing power of the 
private sector is largely untapped in an area of large and growing need. 

Last month, the FDA announced that it was reconsidering whether to 
allow a health claim for folic acid. The standard in the law is that there be 
"significant scientific agreement" on a health claim. The September 1992 



167 



Public Health Service recommendation was certainly based on good science, 
although it clearly wasn't good enough for the FDA at that time. I would be 
very interested to learn exactly what new body of scientific evidence has 
suddenly emerged since January 1993 to convince the FDA that a health 
claim for folic acid is warranted. The CDC publication lists 8 scientific 
studies conducted between 1981 and 1991, all but one of which resulted in a 
reduction in the risk of neural tube defects of at least 60%. According to the 
CDC: 

One of the most rigorously conducted studies was 
the randomized controlled trial sponsored by the British 
Medical Research Council. The study showed that high- 
dose folic acid supplements (4.0 mg per day) used by 
women who had a prior NTD-affected pregnancy reduced 
the risk of having a subsequent NTD-affected pregnancy 
by 70%. 

This was a 1991 trial. A 1989 randomized controlled trial in Hungary was so 
successful that it was stopped before completion by the scientific advisory 
committee because the protective effect of the women taking folic acid was so 
pronounced over those taking the placebo. 

In December of this year, the FDA may finally allow a health 
claim for folic acid and neural tube defects, and American women can begin 
to catch up with their Hungarian counterparts. Meanwhile, about half the 
2500 annual NTD could have been avoided through the use of folic acid. 
Thus, the FDA's delay means that over 1250 serious birth defects could 
potentially have been averted if only the Government's left and right hands 
had worked together and if the supplement industry had been allowed to 
help communicate a truthful and scientifically supported health claim to the 
American people. 

There is one more footnote to this extraordinary episode that bears 
comment. One of the FDA's stated concerns about folic acid is that it may 
mask the occurrence of vitamin B12 deficiency, especially among the elderly. 
The obvious solution to this potential problem is to put appropriate 
information on the labels of dietary supplements of folic acid and to target 
women of childbearing age about the dangers of NTD's rather than to rely on 
a general supplementation of the food supply, which would seem to increase 
the chance that B12 anemia would be masked. 



168 



Mr. Chairman, public health policy on health claims for dietary 
supplements is far too important to be left in the hands of the bureaucrats at 
the FDA with their 40 year history of bias against supplements. The FDA 
claims that their hands are tied by the significant scientific agreement 
standard in the statute. I don't believe that this is what Congress intended, 
but since the Agency believes differently, it is obvious that the Congress must 
change the law if Americans are to have any realistic hope of enjoying the 
preventative benefits of dietary supplements on a timely basis. 

Those who fail to learn from history are condemned to repeat it. Some 
84 years passed between the discovery that limes could prevent scurvy and 
the requirement by the British Government that limes be provided to its 
navy. Dr. Linus Pauling extolled the benefits of Vitamin C decades ago, and 
subsequent research has confirmed the important role of Vitamin C in disease 
prevention. The Shute Institute published good data over 30 years ago on the 
ability of Vitamin E to help prevent heart disease, and the antioxidant 
properties of this vitamin have been increasingly appreciated in scientific 
studies since then. However, the FDA will not allow a health claim for a 
supplement of either Vitamin C or E, and it may be decades before they bow 
to the inevitable. Meanwhile, Americans continue to suffer from preventable 
diseases and our health care costs skyrocket. 

Some very brief remarks about the safety issue are in order. I can be 
brief because even the FDA admits that most supplements are safe. The 
point I would make that there is no absolute safety—virtually everything, 
including oxygen, water and bananas has a toxic intake level— and that we 
must take a broader look at the costs and benefits. I'm sure that you have 
heard about L-Tryptophan. Contamination in some L-Tryptophan led to a 
number of deaths and injuries. Our industry responded by removing L- 
Tryptophan from our products and from our shelves. Yet the FDA allows L- 
Tryptophan in baby foods to this date. As chart 2 illustrates, if absolute 
safety were the only measure, the FDA should never approve a drug and 
barbecues should be outlawed. Similarly, no one should eat shellfish, as 
there were 67 reported incidents of shellfish associated outbreaks of infectious 
disease in the first 11 months of 1992, and only about 5-10% of actual cases 
are reported, according to the FDA. 

Mr. Chairman, in the name of questionable safety concerns and a 
scientific standard that only they claim is unreachable, the FDA is throwing 
the baby out with the bathwater when it comes to health claims for dietary 
supplements. This serves the narrow bureaucratic interests of the FDA, but it 
is terrible public health policy. 



169 



Thank you again for your interest and your leadership in this 
important public health subject. We look forward to working with you and 
your colleagues on the Government Operations and other committees to 
obtain a rational and workable legislative solution that will provide for the 
education of consumers about important and potentially life saving health 
information while, at the same time, protecting them against any valid and 
realistic safety concerns. 



170 



CHART 1 

POTENTIAL SAVINGS IN DISEASE CARE COSTS 

Front Improved Nutrition/Prevention Information Dissemination 



Kellog Report Estimates : 

Respiratory 
Arthritis 
Mental illness 
Alcoholism 
Digestive Disease 
Kidney & Urinary 



Health Studies Collegium: 

Cancer 
Stroke 

Cardiovascular 
Adult Diabetes 
Gingival & Dental 
Neural Tube Defects 
Hip Fracture 



1.4 
0.9 
1.4 
14.5 
1.0 
1.3 



7.0 
23.0 
15.0 
29.0 
43.0 
45.0 

4.0 



$27.8 Billion 



$166 Billion 



With Use of Natural Therapies including Supplemental Nutrients & Herbal Remedies 

Townsend Letter for Doctors: 



Prostate 
Asthma 
Heart Attack 
Osteoarthritis 
Ear Infections 
Ulcer 



2.7 
3.0 
1.0 
1.0 
.5 
1.3 



$8.5 Billion 

TOTAL, SELECTED CONDITIONS = $202.3 BILLION 



171 

Chart 2 

RELATIVE PRODUCT "TOXICITY" 

ANNUAL AVERAGE 

DEATHS : 

Adverse Drug Reactions: 100,000 

Food Contamination: 9,100 

Charcoal Briquettes (Carbon Monoxide): 34 

Household cleaners: 24 

Pesticide poisoning: 12 

Iron poisoning: 6 

All Plants (house plants, etc.): 1 

All vitamins: 

Uncontaminated amino acids: 

Commercial Herbal Products: 



Sources: Calculations based on data from the American Association of Poison Control 
Centers, National Center for Health Statistics, Journal of the American Medical Association, 
Centers for Disease Control. 



172 

Mr. Towns. Ms. Hildwine. 

STATEMENT OF REGINA HILDWINE, DIRECTOR, TECHNICAL 
REGULATORY AFFAHtS, NATIONAL FOOD PROCESSORS AS- 
SOCIATION, ACCOMPAMED BY JOHN BODE, LEGISLATD/E 
COUNSEL 

Ms. Hildwine. Thank you, Mr. Chairman and members of the 
subcommittee for this opportunity. 

I am Regina Hildwine, director of Technical Regulatory Affairs 
for the National Food Processors Association, or NFPA. I am re- 
sponsible for the association's regulatory work with the Food and 
Drug Administration. And with me today is our legislative counsel, 
Mr. John Bode. 

NFPA is the science-based association of the food industry, and 
our 500 members manufacture the Nation's processed-packaged 
foods. NFPA members are now developing new nutrition labels to 
comply with the FDA rules that implement the Nutrition Labeling 
and Education Act of 1990, popularly, the NLEA. The processors of 
meat and poultry products are also adopting a new nutrition label 
to comply with USDA regulations. This is a challenging endeavor 
but an endeavor which the NFPA and the food industry both sup- 
port. 

In June, FDA proposed three rules to regulate dietary supple- 
ment labeling and claims in terms that are closely comparable to 
that for foods. 

Mr. Chairman, NFPA supports the FDA proposed rules. Dietary 
supplements should be regulated in the same manner as foods. 
NFPA believes that there is no scientific basis to consider dietary 
supplements, which supply vitamins, minerals, and other nutri- 
ents, as any different from foods, which provide the same nutrients 
to consumers through slightly different means. 

By way of illustration, food processors often enrich or fortify 
foods with vitamins and or minerals. There are examples such as 
enriched flour which contains the added nutrients thiamine, niacin, 
riboflavin, and iron, according to the specifications in its standard 
identity. 

Many manufacturers of juices and drinks also fortify the food 
with vitamin C. These vitamins and minerals are the same food 
chemicals that are used in many dietary supplements. Food and 
supplement manufacturers both obtain these chemicals from the 
same commercial sources. I haven't even mentioned the most obvi- 
ous comparison, that of fortified breakfast cereal, which I am sure 
you have heard marketed as crispy, crunchy vitamins; and natu- 
rally occurring vitamins in food such as vitamin A and vitamin C 
in citrus fruits, calcium in dairy products, and iron in meats. 

The food industry believes that dietary supplements must be 
held to the same standards as foods. Foods and dietary supple- 
ments compete with consumers' vitamin and mineral dollars, and 
this reason alone demands that the competitive playing field must 
be level. The issue of the level playing field raises the question of 
health claims for dietary supplements. Conventional foods are now 
held to the NLEA standard of significant scientific agreement. 
Though a substantial burden, there is a rational basis for this 
standard. 



173 

The shifting sands of science can confuse and contradict. And 
claims built on shifting sands may be proved over time to be false 
and misleading. Significant scientific agreement reduces the chance 
that permitted claims will be built on shifting sands. NFPA be- 
lieves that dietary supplements should also follow this standard. 

In the interest of a level playing field, NFPA also believes that 
FDA should reexamine the health claims that it will permit to con- 
sider allowing dietary supplements to make certain health claims 
that are now the exclusive province of food: Vitamins A and C as 
related to cancer, and fiber as related to cancer and heart disease, 
provided that supplements can demonstrate that they are equally 
effective as foods. 

Finally Mr. Chairman, NFPA believes that all dietary supple- 
ments must be held to the same standards of safety as foods. For 
more than 85 years, NFPA has been proactive in issues related to 
the safety of processed foods. NFPA has observed over all these 
years that a high degree of safety in food products enhances 
consumer confidence in foods and serves to build trade in those 
foods. 

Adverse episodes undermine consumer confidence, often affecting 
entire segments of the industry, not to mention the consequences 
for the company involved. Because conventional foods and dietary 
supplements compete directly for consumers' nutrient dollars, it is 
imperative that both industries maintain the images of safety and 
credibility in the eyes of consumers. 

NFPA believes that dietary supplements must be as safe as 
foods, must be held to the same regulatory standards as foods, and 
must pass the same scientific tests to substantiate claims as foods. 
This is the only approach in our view that will ensure that the 
competitive playing field will remain level. 

Thank you very much. 

[The prepared statement of Ms. Hildwine follows:] 



174 



National food Processors Assoc:, tion 

1401 New York Avenue. NAY 
Washington. D ( 20005 
202/639-5900 
FAX': 202 '639-5932 



STATEMENT OF THE 

NATIONAL FOOD PROCESSORS ASSOCIATION 

BEFORE THE 

HOUSE COMMITTEE ON GOVERNMENT AFFAIRS, 

SUBCOMMITTEE ON HUMAN RESOURCES AND INTERGOVERNMENTAL RELATIONS 

July 20, 1993 



Mr. Chairman and members of the Subcommittee, thank you for this 
opportunity to provide testimony. I am Regina Hildwine, Director 
of Technical Regulatory Affairs for the National Food Processors 
Association (NFPA) . I am responsible for the association's 
regulatory work with the Food and Drug Administration. 
Accompanying me today is John Bode, Legislative Counsel for NFPA. 

NFPA is the science-based association of the food industry, whose 
500 members manufacture the nation's processed-packaged fruits 
and vegetables, juices and drinks, meat and poultry, seafood and 
specialty products. NFPA maintains three food science 
laboratories which conduct an array of important research related 
to food processing. We very much appreciate this opportunity to 
testify today on the issue of dietary supplements regulation. 

In my remarks this morning, I will touch upon NFPA's views on the 
dietary supplement regulations proposed by the FDA, issues 
related to health claims and safety on dietary supplements, and 
some perspective on the competitive environment for dietary 
supplements and other foods. 

NFPA members are now in the process of developing new nutrition 
labels, to comply with FDA regulations implementing the Nutrition 
Labeling and Education Act of 1990 (NLEA) . Processors of meat 
and poultry products are also adopting a new nutrition label to 
comply with regulations of USDA's Food Safety and Inspection 
Service, which were promulgated under existing authority, and 
which conform closely to the FDA mandatory nutrition labeling 
rules. This is a challenging activity for the food industry, but 
it is also an endeavor which NFPA and the food industry both 
support. Studies have shown that consumers want clear and 
believable nutrition information on food labels, and these new 
rules will deliver that information. 



- 1 - 



WASHINGTON. DC. * DL' BLl N, CAl.I FORN I A * SEATTLE. WASHINGTON 



175 



The food industry also supported the authorizing legislation, the 
NLEA, and expended much time and effort in working with Congress 
so that labeling legislation would provide a level playing field 
among competitors. Once the NLEA was passed, NFPA expended 
considerable scientific and regulatory expertise during the 
rulemaking process to help assure that this complicated law was 
implemented in an effective and reasonable fashion. NFPA now is 
helping to educate both the food industry and consumers about the 
new nutrition label. On May 8, 1994 the mandatory nutrition 
labeling requirements of the NLEA become effective, and mandatory 
nutrition labeling for meats and poultry becomes effective 
shortly thereafter, but already we are seeing new food labels 
that will over time become a significant part of the education of 
American consumers on nutrition and healthful dietary choices. 

Mr. Chairman, with the passage of the NLEA and the conclusion of 
the regulatory process, we now have in place a system that will 
work for the benefit of consumers and the food industry alike. 
While there are provisions of the NLEA that are difficult and 
will be expensive for the members of NFPA to accommodate, 
nonetheless our industry values highly the regulatory certainty 
that now governs food labeling. Our members understand the 
requirements of the NLEA, and they have reallocated resources to 
implement NLEA regulations. Consumers will benefit from the 
uniform meaning of label terms and the consistent information 
conveyed on those food labels. 

In June of this year, FDA proposed three rules, under the NLEA, 
to regulate dietary supplement labeling and claims in closely 
comparable terms to foods. At the same time, FDA announced its 
intention to regulate the safety of amino acids, herbs, and other 
nutritional substances. 

NFPA supports the FDA proposed rules. It is the view of NFPA 
that dietary supplements should be regulated in the same manner 
as foods. Dietary supplements figure prominently in the dietary 
and nutrient decisions of Americans. As such, it is crucial that 
dietary supplements — vitamins and minerals, herbal substances, 
and other nutrients such as amino acids — be regulated in a 
manner consistent with foods under the NLEA to achieve the over- 
arching purposes of the Act. We can not expect to educate and 
empower consumers to make sound dietary choices if supplements 
are not brought within the regulatory regime of the NLEA. 

NFPA believes there is no scientific basis to consider dietary 
supplements, which deliver vitamins, minerals, and other 
nutrients, as any different from foods, which deliver the same 
nutrients to consumers through slightly different means. 

By way of illustration, food processors often supplement foods 
with vitamins and minerals through enrichment or fortification. 
Enriched flour contains the added nutrients thiamine, niacin, 

- 2 - 



176 



riboflavin, and iron, according to the specifications in its 
standard of identity. Many manufacturers of juices and drinks 
add ascorbic acid to fortify the food with vitamin C. These 
vitamins and minerals — vitamin C, iron, thiamine, riboflavin, 
and niacin — are the same food chemicals used in many dietary 
supplements . Both food manufacturers and supplements 
manufacturers obtain these chemicals from the same commercial 
sources. The examples I've noted do not even illustrate the most 
obvious point of comparison: fortified breakfast cereals, often 
considered to be dietary supplements in food form, and marketed 
occasionally as "crispy, crunchy vitamins." 

In FDA's NLEA regulations for food labeling, published this 
January, there are strict provisions for assuring that the label 
declaration of nutrients accurately represents the nutritional 
qualities of the food. There are thorough regulations for claims 
— both nutrient content claims and health claims — for foods 
containing these nutrients. Also, the rules contain misbranding 
provisions, which prohibit a food from stating that, because it 
contains or is absent certain dietary properties, it is adequate 
or effective in the prevention or treatment of any disease or 
symptom. Health claims regulations permit certain statements on 
specific diet-disease relationships. 

New food labeling regulations assure a level playing field for 
conventional foods. The food industry believes firmly that 
dietary supplements must be held to the same standards as foods. 
Conventional foods and dietary supplements compete for consumers ' 
vitamin and mineral dollars, and this reason alone demands that 
the competitive playing field must be level. 

The issue of the level playing field raises the question of the 
basis of health claims for dietary supplements. Conventional 
foods now are held to the NLEA standard of "significant 
scientific agreement among qualified experts" prior to securing 
FDA approval for health claims. Though a substantial burden, 
there is a rational basis for it: the shifting sands of science 
can confuse and contradict, and claims built on the shifting 
sands, claims lacking significant scientific agreement, may be 
proved, over time, to be false and misleading. The standard is 
designed to ensure scientific consensus on the validity and 
interpretation of evidence used to support a health claim. The 
current standard in the NLEA will screen out poorly designed and 
flawed studies, limiting the FDA approval process for health 
claims to the consideration of sound, objectively obtained 'data. 
This standard is a critical component of a regulatory system 
intended to assure the delivery of reliable and useful 
information to the consumer. "Significant scientific agreement 
among qualified experts" reduces the chance that permitted claims 
will be built on shifting sands. NFPA believes that dietary 
supplements should follow the same standard. 

- 3 - 



177 



In the interest of the level playing field, NFPA also believes 
that FDA should reexamine the health claims it will permit, to 
consider allowing dietary supplements to make certain health 
claims that are now the exclusive province of food: vitamins A 
and C as related to cancer, and fiber as related to cancer and 
heart disease. In addition, any health claims regulation related 
to folate and neural tube defects should consider dietary 
supplements on the same footing as food. The FDA rule permitting 
calcium-osteoporosis claims does appear to apply equally to 
supplements already. 

Finally, NFPA believes firmly that all dietary supplements must 
be held to the same standards of safety as other foods. Without 
adequate FDA regulation, consumers may be enticed into over 
consumption of certain nutrients contained in dietary 
supplements, and thus run the risk of suffering from acute or 
chronic toxicity. There are many identifiable examples of 
nutrient toxicity: excessive zinc intake can interfere with the 
body's ability to absorb another necessary nutrient, copper, 
which may lead to severe anemia and death, and there are 
indications that consumption of zinc can have a negative effect 
on total cholesterol by decreasing HDL cholesterol levels without 
reducing other cholesterol component levels; over 
supplementation of iron in the diet poses a special risk to 
children and to those with genetic tendencies to hemochromatosis; 
selenium can be very toxic at low doses and a mislabeled 
supplement containing this nutrient resulted in the deaths of 
thirteen individuals in 1984; excess consumption of vitamin B. 
can cause neurotoxicity; and people with undiagnosed 
abnormalities of calcium metabolism who consume high calcium 
intakes could develop hypercalcemia, which can prevent the normal 
repair of microfractures in bones and lead to fragility. From a 
health perspective the greatest concern may be the over 
consumption of amino acids. The Federation of American Societies 
for Experimental Biology (FASEB) concluded that the current state 
of scientific understanding does not permit the establishment of 
safe upper limits on the consumption of amino acid supplements, 
and that certain population groups should only consume these 
products under explicit medical supervision. 

It is important to the food industry that supplements and the 
components of supplements be regulated in a manner similar to 
food additives. Many nutrients in dietary supplements also occur 
naturally in foods, or are added to food products during the 
manufacturing process. If misused or over consumed due to 
inadequate safeguards, these normally safe substances can lead to 
acute or chronic toxicity. Such events could tarnish the value 
of specific nutrients or other substances in the eye of the 
consumer. Likewise it is important that, like foods, supplements 
be manufactured under good manufacturing practices to assure that 
impurities or other contaminants do not render a product 
injurious to human health. 

- 4 - 



178 



The food processing industry fears that highly publicized 
episodes of injury or illness resulting from inadequately 
regulated supplements may turn consumers away from foods bearing 
safe and beneficial quantities of the same substances. For 
example the addition of dietary fiber to foods can substantially 
enhance the nutrient profile of a particular food for the benefit 
of consumers. However, ingesting isolated fiber in the absence 
of food can reduce the intake of essential nutrients. Of even 
greater concern is the possibility of immediate injury that can 
result from consumption of soluble fiber that is not fully 
hydrated: soluble dietary fiber supplements can be especially 
dangerous. If a soluble fiber supplement is not fully hydrated 
before consumption, then the fiber once consumed can expand 
dramatically in the stomach and intestine as it becomes hydrated. 
This increased bulk can lead to intestinal obstruction and excess 
fermentation. Recently the use of guar gum supplements, also a 
common constituent of many processed foods, produced severe 
gastrointestinal illness for several consumers, and resulted in 
the recall of the product. 

It has been NFPA's experience over 85 years that a high degree of 
safety in food products enhances consumer confidence in foods, 
and serves to build trade in those foods. Adverse episodes 
undermine consumer confidence, often affecting entire segments of 
the industry — not to mention the consequences for the company 
involved. Because conventional foods and dietary supplements 
compete directly for consumers' nutrient dollars, it is 
imperative that both industries maintain the same images of 
safety and credibility in the eyes of consumers. Any loss of 
credibility, or failure of public confidence, can mean literally 
hundreds of millions of dollars in market disruptions to the food 
industry. 

Advocates for the dietary supplement industry may contend that 
supplements are distinct and apart from foods, and certainly 
marketing strategies for supplement products may try to create 
the illusion of such differences. Nonetheless consumers expect 
and believe that FDA regulation of dietary supplements is as 
comprehensive and effective as it is for conventional foods. The 
consumer has no reason to know or expect that supplements may 
represent a class of products manufactured and sold under a 
regulatory regime that is less rigorous or effective than that 
which governs food products. 

NFPA believes that dietary supplements must be as safe as foods, 
must be held to the same regulatory standards as foods, and must 
pass the same scientific tests to substantiate claims as foods. 
This is the only approach that will ensure the competitive 
playing field remains level. 

Thank you. 

- 5 - 



179 

Mr. Towns. Thank you, very much. Let me thank all of you for 
your testimony. 

Let me begin with you Mr. Cordaro and also Ms. Whittekin. Do 
you agree with Ms. Hildwine that FDA should apply the same 
standard of proof for health claims to dietary supplements that 
they do to food? 

Ms. Whittekin. I will answer first, since you are looking in this 
direction. 

Well, yes and no. In one respect, we think that there certainly 
are a lot more claims that should be allowed for food because the 
evidence is just so substantial. 

And we are worried because our industry also sells food for 
which we aren't able to make some very responsible claims in that 
area. 

However, there is a difference. I think we should hold foods to 
the highest standard of all because that is not an optional thing. 
Everybody has to eat. People eat for a variety of reasons that have 
nothing to do with what the nutritional contents are. There are 
some people that don't even read the ingredient panels. 

Whereas, supplements are taken intentionally and often to ad- 
dress a particular need. That is not part of public health policy as 
a whole. When you start fortifying the entire food supply, it brings 
up other considerations. I think, rationally, when we look at the 
hundreds of claims that are available to be made because they are 
substantiated, when you get into the area of herbs and some of 
them don't seem to lend themselves handily to the food supply as 
a whole. 

If it were possible to sit down with the FDA and craft a reason- 
able policy that would protect foods the way they need to be pro- 
tected and allow for these claims. And if I could address the pile 
of products that was out here earlier, a lot of those products are 
not as misleading as it sounds. We used to think that it was just 
outrageous to say that zinc would promote your immune function. 
But actually that was 1 of the 10 health claims that Congress 
asked the FDA to look at because there is so much substantiation 
that zinc helps the immune system of the elderly. A lot of this is 
not unknown. And I am not able to look at the backs of the labels 
and say which is which. But it is easy to throw them all in the 
same bag. It is a lot more complicated than is being painted. 

Mr. Towns. But you do agree that some of it is misleading? 

Ms. Whittekin. Absolutely. There is fraud out there, and it is 
evident to our industry because it does lend discredit to the good 
products that are out there. 

But how do you protect against that without throwing the baby 
out with the bath water, which is what is being proposed by the 
FDA? 

Mr. Cordaro. I am going to be unique and answer your ques- 
tions rather directly. 

Mr. Towns. That would be unique. 

Mr. Cordaro. I believe that conventional foods and dietary sup- 
plements should adhere to the same standard. 

However, I believe that we ought to focus on the fact that the 
issue is not really the standard but the interpretation of the stand- 
ard by the Food and Drug Administration. 



180 

I believe that one of the functions of this oversight hearing 
should be to see if FDA has appropriately interpreted the intention 
of Congress. For example, if we listen to Dr. Shank this morning 
and if we've listened to Mr. McNamara and Mr. Silverglade, the 
issue is one of when do you make a decision about being able to 
convey information to the consumer? 

I use the notion of an information continuum as a way to try to 
describe that. If you look at zero as no information on one end and 
10 at the other end — scientific consensus as you asked this morn- 
ing — it is our judgment that FDA has been making that decision 
much closer at the 10 level, at the consensus level. And while it 
is true that at the zero level or one level, very preliminary informa- 
tion, it would seem to be inappropriate to allow a health claim in 
those areas. When you have gone beyond and you are at the six, 
seven, and eight level, it would seem that you have way passed the 
notion of preliminary and that the whole tone and direction of 
where the scientific evidence is leading to is suggesting that con- 
sumers ought to have access to that information. So, while we 
would say that we should adhere to the same standard for many 
of the reasons that were mentioned, we do believe that FDA should 
be directed to change the way they are interpreting the standard. 

Ms. Whittekin. Perhaps an example would help. Vitamin E, as 
an antioxidant in the prevention of heart disease, is one of the 
claims that the FDA may get around to approving in the next few 
years. 

There has been what most people consider a scientific consensus 
about that for quite a while; the evidence has been mounting for 
40 years. The question is how much is enough proof? 

Mr. Towns. Let me ask quickly, Ms. Hildwine: Do you agree with 
Mr. Cordaro's assessment that FDA has been too conservative in 
its interpretation of significant scientific agreement? 

Has the agency, in fact, not approved certain health claims that 
it should have approved? 

Ms. Hildwine. Well, Mr. Chairman, there may be some in- 
stances where that has happened. We do expect to see some move- 
ment from the agency in the future. But we also have to keep in 
mind that we are talking about the health of consumers where peo- 
ple cannot necessarily evaluate the truth or falsehood of a claim 
relative to their health. 

You know, consumers aren't scientists, and they can't always 
evaluate this. I would say that perhaps FDA may have been too 
conservative, but they are to be applauded for being cautious. 

Mr. Towns. Thank you very much. 

I yield to Congressman Schiff, the ranking minority member of 
the subcommittee. 

Mr. SCHIFF. Thank you, Mr. Chairman. I appreciate that. 

Let me be slightly devil's advocate on both sides. Ms. Hildwine, 
you advocated — and I believe were supported by Mr. Cordaro — the 
concept that in labeling the standards for dietary supplements and 
food ought to be the same. 

Is that right? 

Ms. Hildwine. That is right. 



181 

Mr. Schiff. Mr. McNamara gave an example from a previous 
FDA regulation going back a number of decades that suggests 
there is a difference between the two. 

Are you advocating a change in what has been the approach for 
years? 

Ms. Hildwlne. I would have to check the Code of Regulations. 
But if my memory serves me, it is FDA regulations other than 
amended by NLEA regulations. But I would have to check that, be- 
cause the two sectors of the industry — of the ingestible nutrients 
industry; let's call it that — they do compete. We feel that the stand- 
ards should be as close to similar as absolutely borne out by the 
science. 

Mr. Schiff. Let me take up one other matter on the other side. 
What is becoming clear to me, I should say by way of introduction, 
is that there are two separate issues. One is the regulation of the 
substances as such that might be in dietary supplements or any- 
thing else, and a regulation of labeling that is presented for dietary 
supplements is another concept. 

If I understood one of the previous panelists — and I am looking 
at Ms. Whittekin and Mr. Cordaro — the supposition was made that 
the attack — or the suggestion that the FDA wants to make certain 
dietary supplements into a drug for prescription purposes which 
was alluded to in one or both of your statements, was, in fact, a 
diversion, a diversion away from the proper labeling of the nutri- 
tional benefits of dietary supplements. That is what I heard from 
the witness. 

So let me focus specifically on the idea of regulation of the sub- 
stance. Do you have any — what is your concrete basis for saying 
that the Food and Drug Administration would, if it could, attack, 
if you will, the dietary supplements themselves, not the labeling 
but the substances, and do things like either ban them or make it 
more difficult to acquire them through some prescription require- 
ment? 

I say that particularly in view of the FDA's representatives in 
the first panel saying that was not their idea. 

Ms, Whittekin. Some of the talk of scare tactics is based on the 
fact that those of us close to the situation are, indeed, scared. We 
have talked to the FDA and read the advanced notices. And in 
their quotes, they have trouble telling the difference between the 
proper regulation of the substance and that of the claim. 

And the food additive theory that they have used to take sub- 
stances off the market is a good case in point. They don't seem to 
want to have to make a case that a substance is unsafe or improp- 
erly labeled. It is easier to get rid of it and they have done that 
with product after product. And a lot of this is based on a 40-year 
history of actions and prejudices such as making a huge chain of 
nutrition supplement stores take books out of their stores; some- 
thing like a book burning. 

We were hoping that, as they changed personnel, that they 
would change. They talk about flexibility; but every time we get to 
the table to talk about it, there is no movement on their end of the 
table. They have said that all supplements, with the exception of 
RDA vitamins and minerals, all dietary supplements start out with 



182 

the presumption that they are food additives or drugs and you have 
to prove that they are not. And that is an impossible burden. 

Mr. Schiff. Where have they said that? 

Ms. Whittekin. I have documents with me. I don't remember the 
particular citation, but it is from their own press releases and 
speeches. 

Mr. Schiff. Mr. Cordaro, do you desire to respond to that? 

Mr. Cordaro. Yes. In the comment that was made this morning 
by one of the FDA people, he seemed to be attempting to sort of 
soothe the 100 million consumers of supplements that they 
shouldn't take this advance notice of proposed rulemaking too seri- 
ously. It was just an idea that was thrown out, and they want to 
see how people respond to it. But we do take it very seriously, be- 
cause for vitamins and minerals, they have suggested that they 
would establish a dietary supplement limit that would not allow a 
manufacturer to market a product that was much more than what 
the RDA level is as established by the National Academy of 
Sciences. 

The intriguing issue is that all of the scientific data is showing 
that it is more generous consumption of micronutrients that helps 
to reduce the risk of disease. It is also rather intriguing because 
most of the vitamins and minerals are already generally recognized 
as safe by the Food and Drug Administration. 

So while I heard what the gentleman said this morning, I am in- 
trigued as to why they have made the effort that they have made 
in putting forward the advance notice of proposed rulemaking. I am 
quite concerned about what might come out the other end because 
of the history of the way they have dealt with supplements in the 
past. 

Mr. Schiff. I thank the witnesses and yield back. 

Mr. Towns. I yield to Congressman Payne. 

Mr. Payne. Mr. Chairman, I have no questions, other than the 
fact that in testimony — and it has been reiterated by Ms. 
Whittekin — about this 40 years of hostility between the dietary 
supplement industry, of which you are a member, and the FDA. 
And it appears to me that if that seems to be the attitude or the 
prevailing situation now, it seems like it is very difficult for you 
and the FDA and the industry to sit down and try to arrive at a 
consensus. 

And I do see that there are instances, two or three cited. But do 
you envision the relationship between your organization and that 
agency improving? 

Ms. Whittekin. Well, on a personal level, we get along just fine. 
It's iust when it gets down to getting any business done, we don't. 

I near from many of our members that they contact the FDA to 
try to get approval for the language that is on the label that might 
include warnings of use, and they are told they have to take that 
off. If they put the warnings on, it puts it into another category. 
It's things like that that we are having trouble working out and we 
wish to have more input on self-regulation. 

The industry is working hard trying to self-regulate. It is a fairly 
new industry; and as we are maturing and are trying to adopt, as 
CRN has, very comprehensive standards including ones for claims 
and things that we are concerned with here today, we have asked 



183 

for the cooperation and input of the FDA. They seem to have no 
interest in anything that we are doing. And I would contend that 
the country cannot afford to regulate everything for us. The indus- 
try should do the bulk of the regulation for itself. It's much more 
cost effective and have the FDA oversee ours. 

But they have seemed to show no interest, and that's the kind 
of thing that we have a hard time dealing with. The attitude 
change may have to be legislated. 

Mr. Cordaro. I would like to add to that, Mr. Payne, because I 
am very concerned as a consumer, and I am very concerned as 
someone who has worked in this town for almost 30 years. I have 
seen the evolution of the science to where I am very excited about 
where it might lead. I am concerned about the hostilities that Ms. 
Whittekin mentioned. 

And the reason I was interested in taking part in this hearing 
was to ask you all to encourage the industry and the Food and 
Drug Administration to sit down and to find a way to resolve our 
problems without rattling swords and sabres and without trying to 
resolve these problems in 8 second sound bytes on the evening 
news and without hurling rhetoric at each other. 

We not only have the 100 million consumers that use dietary 
supplements to be concerned about but the other 160 million or so 
who don't and probably should be using these products because 
they could improve the quality of their health and help us to re- 
duce the health care costs in this country. 

If there is anything that this subcommittee can do to find a locus 
or forum to sit down and get that discussion going, I think that will 
go further to resolve more problems than whatever legislation 
might be passed. 

And I have worked on the Hill also. Sometimes when you pass 
it up here and it gets interpreted downtown, you don't recognize 
the law that was passed. So I think if we can correct some of those 
mindset problems that exist within the agency and the industry, 
we will be a long way toward solving some problems. 

Mr. Payne. Thank you. 

Any comment on the agency and the relationship that you have 
had? 

Ms. Hildwine. I would be happy to, Mr. Payne. NFPA was 
founded in the early years of this century to help support the idea 
and the perception of the safety of processed foods. At that time it 
was canned foods. We used to be the National Canners Association. 
And over the years we have worked well, I believe, with the FDA 
providing them with science and also working to solve problems. 

I would endorse that approach; that it is very productive on both 
sides. Often, the regulatory agency needs to be — needs to have the 
attention of certain elements of science that the industry may be 
aware of. 

Mr. Payne. Mr. Chairman, I hope that that is noted and perhaps 
you might be able to make a movement to take that step together 
to see if there could be some negotiation or meeting of the mind. 
And perhaps a number of these problems that are here might be 
able to be worked out. 

Ms. Whittekin. Mr. Payne, a footnote on that. I envy the rela- 
tionship that the food companies and the food trade associations 



184 

have had. And we do feel like step children because we see other 
industries that operate in that fashion, and that is our desire too. 

Until the mindset changes, we can take 1,200 studies on garlic, 
and we can't get a hearing. It's got to be something more than put- 
ting everybody in a room and turning us loose. 

Mr. Payne. You didn't want to bring it in the hearing, did you? 
Maybe that is the problem. 

Ms. Whittekin. I have done that before. 

Mr. Towns. Ms. Whittekin, let me ask you one final question 
that is sticking with me. In your statement, you indicated that 
there were no deaths between 1983 and 1990. And I can't help but 
think about the iron supplements in terms of children and the poi- 
soning of children. 

How do you ignore that? There seems to be a discrepancy here. 

Ms. Whittekin. I'm glad you brought that up. Iron deaths are 
on there. Vitamins are the zero. Iron is the six. These are 
poisonings with a pharmaceutical product where the parent has not 
been responsible keeping the cap on and the child has eaten them. 
Iron is one of the things that FDA proposes to take away because 
of the safety problem. It is something that is needed for pregnant 
women, particularly. 

The first draft of a paper that I did for the Congressional Re- 
search Service briefing, I didn't have the iron figures. But they are 
on subsequent issues. We are not trying to dodge that. I don't think 
it is part of what is at issue here. Anything can be toxic. You can 
overdose on bananas. 

In the case of iron, we have already had meetings with Ms. 
Stark's office in trying to address that problem. And I think we are 
way ahead of the game on that because our industry has required 
much from our manufacturers along that line. And I think we have 
taken more steps already than most. We have made it a require- 
ment of our exhibitors at our trade shows that they meet some very 
strict requirements on iron. So I think self-regulation can work in 
that area. 

Mr. Towns. Thank you very much. 

Mr. Payne. Mr. Chairman, one quick question. 

Let me ask this question. And I asked the person on the other 
panel. How could the industry sort of look the other way when — 
I guess, you saw some of those displays that were put up by the 
previous panel. And I think I asked the gentleman from the indus- 
try about his opinion, shouldn't the industry be a little more con- 
cerned about — those are the things that show up. 

We had in New Jersey something called the PRG system in 
health care. And there was a wrist that was broken, and it cost like 
$20,000 because something that happened went wrong and that 
was what people talked about rather than the benefits of a prospec- 
tive reimbursement system and all payers and so forth. 

We all know a government is best which governs least; but when 
there is no self-regulation, then you see the government must step 
in. The FDA evidently has enough to do without looking for new 
things to do. New industries come up, so, therefore, you want to 
look at them. I know you can't force a company to be responsible. 
But if some noise could be made by the industry, some of those 
products were disgraceful in what they said. But when the industry 



185 

looks the other way and has shown it is not capable of self-regula- 
tion — in every instance, all the way down the line — that is when 
the government has an obligation to step in. 

Ms. Whittekin. I couldn't agree more. And we are making ag- 
gressive moves in that direction. It's very difficult though, if we 
don't have something like we are setting up, a panel of scientists. 
It's hard for one company to point at another company and say, 
"Don't do that." We are setting up a panel of independent scientists 
that can review these claims for accuracy. Because, as I said, there 
is a lot of it that is misunderstood. 

A lot of those are also not disease claims. A lack of energy is not 
a disease, per se. So if somebody buys a B vitamin supplement and 
finds it doesn't give them energy, they can go and get their money 
back. 

I think we have to maintain a healthy respect for the market- 
place on the things that are not disease claims where health is not 
at risk and the economic harm is in the under $10 range and peo- 
ple have a remedy where they can get their money back. What we 
are focusing on and would like the FDA to do the same, is to put 
most of our emphasis on where the most harm is done. And this 
is where the claims are being made for the prevention of AIDS or 
cancer or anything that is not substantiated. That is definitely 
fraudulent and misleading. 

That is where we are starting, but 

Mr. Cordaro. Mr. Chairman. Can I close it off with one quick 
comment? The industry should be doing more to police itself. As 
much as we are doing, we need to do more. In order to be effective 
though, we are going to have to have a hand from the Food and 
Drug Administration so that they are willing to recognize that 
what we are doing will have validity in the marketplace and that 
they will work with us. 

CRN has voluntarily put dosage limits on several of its nutrients 
in its manufacturers' products, not because FDA told us to but be- 
cause we felt it was the prudent thing to do. As a result of what 
we have done, FDA has not had to take regulatory action in those 
areas. 

We would welcome it, Mr. Payne, but we would like to have a 
hand from FDA. 

Ms. Whittekin. In the absence of rules, that is the big reason 
why there is this confusion. The FDA has not made their intentions 
clear since 1976. Nobody knew what the limits were, and that is 
why there is confusion. As an industry, we are going to set some 
limits and hope that the FDA will meet with us on them. 

Mr. Towns. Let me thank all the members of the panel. Thank 
you very much for your testimony. Ms. Hildwine, Ms. Whittekin, 
and Mr. Cordaro, thank you very much. 

I would now like to call our fourth panel, a panel of scientific ex- 
perts on these matters. We will hear from Dr. Gladys Block of the 
University of California, Berkeley; Dr. Irwin Rosenberg of Tufts 
University; Dr. Lynn Bailey of the University of Florida; Dr. Esther 
Sternberg of the National Institute of Mental Health; Mr. Robert 
McCaleb of the Herb Research Foundation; and Dr. Ryan Huxtable 
of the University of Arizona. 



186 

If you all would please stand, we swear in our witnesses, as I ex- 
plained earlier. Will you please raise your right hand, all of you. 

[Witnesses sworn.] 

Mr. Towns. Please take your seats, and let the record show that 
the witnesses answered in the affirmative. 

Let me begin by saying that the full text of your written state- 
ment will be inserted in the record. I ask that you summarize your 
statements in approximately 5 minutes. The green light will be on; 
and when the green light goes off, the red light comes on and that 
means your 5 minutes are over. 

I know you might say that somebody else didn't pay any atten- 
tion to that, but we would like you to pay attention to the light. 
When the green light goes off and the red light comes on, please 
try to end your statement so we will have time to ask questions. 
Thank you very much. 

First, I ask Dr. Block if you would begin. 

STATEMENT OF GLADYS BLOCK, Ph.D., UNIVERSITY OF 
CALIFORNIA, BERKELEY 

Dr. Block. Thank you, Mr. Chairman. If I could give you a pre- 
view, basically, I would like to show you that I think that the evi- 
dence of benefit is enormous. The evidence of a need for dietary im- 
provement in the public is very great. The evidence of harm is min- 
uscule in my opinion. And, therefore, the balance of the regulatory 
effort by FDA is vastly out of proportion and is misjudging the 
risks and benefits. 

First let me just say that I don't know that we appreciate how 
rapidly this information is expanding. It is expanding enormously. 
In 1982, the National Academy of Sciences published their report, 
Diet, Nutrition and Cancer. Since then, 175 epidemiologic studies 
have been published on antioxidants or their food source and can- 
cer. In 1989, the Surgeon General published Diet and Health. Since 
then, 75 such studies have been published. 

I believe any opinion formed before the prior 5 years is hope- 
lessly out of date. And the trouble is that most of us are hopelessly 
out of date. I can't keep up with this one small area, let alone other 
nutrients and other diseases. I think it is hopeless and maybe inap- 
propriate to expect FDA to keep up with it. 

And I don't actually believe that the nutritional and medical au- 
thorities that are often quoted have kept up with this, not because 
they don't wish to but because it is just happening so rapidly. 

This is just a summary from a review that I did. And I just want 
to point out that for all of these different cancers there is substan- 
tial evidence of benefit. The ratio of significantly protective to no 
effect is overwhelmingly in the direction of a significant effect. The 
magnitudes of the effect are twofold. That is, that people in the 
lower end of the distribution have 2 to 3 times the risk of develop- 
ing cancer as the people in the upper end. There is evidence, sub- 
stantial scientific evidence, in my opinion, for a lot of these. And 
this is a tenth of the list that one could adduce if one had time, 
including things like immune function, including AIDS-related dis- 
ease. A lot of the substances that were put up here to some ridicule 
actually have some evidence of scientific effects. 



187 

There are strong effects, twofold, threefold effects. There are very 
large segments of the population, like a quarter or third of the pop- 
ulation, and the potential public health effects are huge in my opin- 
ion. 

Now, sometimes it is said that all we need to do is eat a well- 
balanced diet. And I would like to point out that we're far from 
that. This is a large national survey of 12,000 adults. On the day 
of the survey, 40 percent of the population had no serving of fruit 
or fruit juice; 80 percent of the population had not a single serving 
of a vegetable rich in vitamin A or vitamin C. The National Cancer 
Institute says we ought to eat five servings of fruits and vegetables; 
9 percent of the population does that on any given day, and only 
5 percent of the African American population. 

And if we were to look at the vitamin intake — I won't take the 
time to show you that — but that would show that substantial seg- 
ments of the population, like a quarter or even a half, are not even 
getting the RDA, whereas epidemiologic data is suggesting that 
more than the RDA might be beneficial. 

Now, what about the magnitude of the risk, the magnitude of 
supplement use, and how much we should be worried about this? 
This is another national survey, 20,000 adults. If you are talking 
about use any time, yes, about 50 percent of the population has 
taken a supplement. But if you are talking about use every day, 
which is the only likelihood of harm, it is only about 23 percent of 
the population that does it. 

African Americans take supplements less than whites. Older peo- 
ple take supplements more than younger people. As has been said 
earlier, it's the more affluent who are taking supplements, not the 
people who are likely to be misled. 

Arid let's look at this. Of all those supplement users, the vast 
majority are taking multiple vitamins, just RDA-type levels. The 
number of people who are actually taking single vitamins — this is 
1987 data — are very small; 4 percent of the population takes vita- 
min E on a daily basis. And the proportion of the population that 
take the sort of far out things — which I would like to come back 
to later, that we saw on the table today — is bound to be much 
lower than that. 

I will stop there. 

Mr. Towns. All right. Thank you very much. And the red light 
is on. 

[The prepared statement of Dr. Block follows:] 



188 



1 TESTIMONY, JULY 20, 1993, BY GLADYS BLOCK, PH.D. 

2 TO HOUSE GOVERNMENT OPERATIONS SUBCOMMITTEE 

3 Table of contents 

4 Overview 1 

5 Definitions, Limitations 2 

6 Evidence for a beneficial role is strong 2 

7 What is the "right" amount of each nutrient? 5 

8 How adequate are typical American diets? 7 

9 Supplement use 8 

10 Toxic levels 9 

1 1 The evidence is increasing explosively 9 

12 Public policy and FDA's role 10 

13 Tables 1 & 2 12 

14 Appendix I: Are clinical trials the answer? 14 

15 Appendix II: Reservations about epidemiologic data 18 

16 Appendix HI: Laboratory data support antioxidant role 22 

18 OVERVIEW 

19 There has been an explosion of scientific interest and research on the role of nutrition 

20 in health, producing literally hundreds of epidemiologic studies and perhaps thousands of 

21 biochemical and other laboratory studies. Thus, any point of view formed prior to the last 

22 half decade is seriously out of date. Although I will focus on the area of antioxidant nutrients 

23 and cancer risk, I believe it serves as a prototype for numerous nutrients, and numerous 

24 diseases. There are several key points: 

25 1. The evidence of a beneficial role for these nutrients is extraordinarily extensive. 

26 2. Many Americans are not consuming even minimal, let alone excessive, amounts of 

27 nutrients. 

28 3. There is no evidence that supplement users neglect their diet or other health care — 

29 quite the contrary. 

30 4. For most nutrients, credible evidence for serious risk is minimal. 

31 5. The evidence of benefit is increasing explosively, and conclusions formed a decade 

32 ago are insufficient to inform us. 

33 6. FDA's role in protecting public health would be much more valuable if focussed on 

34 ensuring quality of supplements, and providing consumers with information. 

1 



189 



1 DEFINITIONS, LIMITATIONS 

2 Micro nutrients: vitamins, minerals and other small dietary components 

3 Macron utrients: calories, fat, protein and carbohydrate 

4 Antioxidants: micronutrients that can scavenge or block the damage caused by oxidation. 

5 Antioxidants include vitamins C and E, beta-carotene and other carotene-like 

6 molecules. 

7 My remarks on health benefits and risks are focussed on micronutrients, and 

8 particularly on the role of antioxidants in reducing the risk of cancer. However, the argument 

9 should be interpreted as much broader than that. For example, there is growing evidence for 

10 numerous other associations: 

1 1 * folic acid and cancer 

12 * folic acid and neural tube birth defects 

13 * antioxidants and heart disease 

14 * antioxidants and cataracts 

15 * numerous other associations - toxemia of pregnancy, neurologic diseases, many 

16 others. 

17 Thus, although the data below refer to antioxidants and cancer, it is legitimate to see it 

18 as a paradigm for numerous other nutrient-disease relationships. In addition to the scientific 

19 issues, some public policy issues raised by the micronutrient observations may apply equally 

20 to other dietary components, including amino acids, herbs and similar substances. I address 

21 these below under the section "Risks, Benefits and Public Policy". 

22 Is ovemutrition the only problem? 

23 There is a fairly widespread belief that the only nutritional problem of public health 

24 importance in the United States relates to ovem utrition - that people are obese, there are 

25 health effects, and therefore we should get them to eat less fat and fewer calories. While the 

26 latter part may be true, I profoundly disagree that ovemutrition is the only serious health 

27 problem. I will present data later in this document to demonstrate that there is considerable 

28 undernutrition in the United States - inadequate intake of vitamins and minerals ~ and that 

29 this has health consequences at least as important as those associated with obesity. 

30 L THE EVIDENCE FOR A BENEFICIAL ROLE FOR SEVERAL VITAMINS AND 

31 MINERALS IS VERY STRONG 

32 a) What kinds of data exist on the role of nutrients, and how should we interpret 

33 them? 

34 1) Epidemiologic data: Studies in human populations, or in persons with and without a 

35 disease, to determine what dietary factors might be related to risk of disease. 



190 



1 2) Laboratory data: Biochemical, immunological or animals studies on the role of nutrients in 

2 preventing oxidation, affecting immune function, influencing disease. 

3 Either one of these kinds of evidence, by itself, leaves us uncertain about how to 

4 interpret the data. The important point is that today, both lines of evidence are converging. 

5 are pointing to the same conclusion that many micronutrients are extremely important to 

6 human health. 



7 b) The epidemiologic data are extraordinarily consistent 

8 For no relationship besides smoking and lung cancer is the evidence as abundant 

9 and consistent: The nutrients contained in fruits and vegetables reduce the risk of 

10 cancer. 

11 In a recent review, I examined every epidemiologic study that had been conducted, 

12 worldwide, on the possible role of fruits and vegetables or their antioxidant nutrients and 

13 cancer risk. This included approximately 200 studies, in regions as diverse as China, the 

14 Netherlands, upstate New York, rural Louisiana, Texas, Hawaii, etc. The cancer sites 

15 included almost all major cancer types, including lung, breast, colon, cervix and many others. . 

16 For every single cancer site except one, the overwhelming majority of studies found a 

17 statistically significant reduced risk with higher intake . 

18 From an antioxidant nutrient perspective, the evidence is extraordinarily consistent. Of 

19 lung cancer studies, 29 of 3 1 found significant protection associated with high dietary intake 

20 of fruits and vegetables rich in carotenoids or vitamin C. Of stomach or esophageal cancer 

21 studies, 15 of 15 that calculated vitamin C intake found statistically significant protection; 

22 three-fourths of studies that examined only foods found protection from consumption of 

23 vitamin C-rich foods, and here we refer specifically to rich sources such as citrus, not simply 

24 to any fruit. Indeed, of 10 major cancers (lung, larynx, oral, esophagus, colon, rectum, 

25 pancreas, stomach, cervix, bladder), 33 of 46 studies that calculated vitamin C intake found 

26 statistically significant reduced risk with high dietary intake and essentially aU were in the 

27 protective direction. And of 29 additional studies that examined only fruits rich in vitamin C, 

28 21 of 29 were statistically significandy protective. Of all the studies at these cancer sites that 

29 have examined either vitamin C, vitamin E or beta-carotene or their rich food sources, 

30 approximately 160 of 180 have found significant protection. And as noted elsewhere, many 

31 of these were in populations that did not have the correlated behaviors that come to mind. 

32 The increased risks were not small, but usually a doubling or even tripling of cancer 

33 risk for people with lower intake, compared with those with higher intake. 

34 The increased risks were not just among tiny minorities of the population, but very 

35 large population segments, the lower one-fourth to one-third. One researcher even suggested 

36 that "the large majority of the population may be increased risk compared with the small 

37 minority with a large vegetable intake." 



191 



1 c) All right, we agree about fruits and vegetables, but how do we know which (if 

2 any) nutrient is the effective one? 

3 A key problem faced by the FDA is that epidemiologic data are based on people's 

4 intake of foods ("How often do you eat broccoli?"), but many different nutrients come in 

5 foods. Understandably, FDA is reluctant to attribute the benefit to one particular nutrient, 

6 when there are hundreds of potentially effective components in those beneficial foods. The 

7 result is a Catch-22: 

8 The catch-22: Can't prove it's vitamin C because it might be beta-carotene; can't 

9 prove it's beta-carotene because it might be vitamin C; can't prove it's either one 

10 because it might be folic acid. 

1 1 Such an impasse could permanendy prevent FDA from ever being able to rule favorably on a 

12 role for any of the potential nutrients individually, or even for a class of nutrients such as 

13 antioxidants. 

14 * One supposed way out of such an impasse, clinical trials, is discussed in Appendix I 

15 below. The bottom line: such trials will answer only a limited and narrow set of 

16 questions, and will not help us with most of the nutrient-benefit questions now facing 

17 us. 

18 * Reservations and challenges to interpreting epidemiologic data are discussed in 

19 Appendix II. The bottom line: All dietary data are imperfect, but conclusions are 

20 nevertheless extremely consistent 

21 But getting back to FDA's problem: How can it appropriately regulate vitamin C, 

22 without knowing for certain whether protective effects are due to vitamin C, or to vitamin E, 

23 or to folic acid...? I suggest that there are several inappropriate assumptions in this question. 

24 The search for a 'magic bullet', for the right nutrient, comes from a medical 
23 model of the right drug to kill a microbe and cure a disease. Public health, 

26 health promotion, demands a different model. There is no one right nutrient 

27 - One nutrient may be more important in one disease (e.g., vitamin C and oral 

28 cancer), and another more important in another disease (e.g., carotenoids and 

29 lung cancer, vitamin E in heart disease). All are important, and trying to 

30 identify the "right" nutrient that prevents a particular disease study is poindess 

31 for public health in general. 

32 - There is good evidence that they work together, supporting and reconstituting 

33 one another. On the other hand, to some extent they may be able to substitute 

34 for one another. 



192 



1 Clearly, there are hundreds of compounds in foods, a large number of which are likely 

2 to have biological effects, things such as isothiocyanates, flavonoids, etc. I don't disagree 

3 with this, and indeed, I spend much of my time promoting increased consumption of fruits 

4 and vegetables. However, the fact that other compounds are likely to also have an effect 

5 should not blind us to the data that certain compounds almost certainly do have an effect, 

6 namely the antioxidant vitamins, vitamin C, vitamin E and beta -carotene. The laboratory 

7 evidence is extremely clear . The epidemiologic evidence is extremely consistent. So 

8 although fruits and vegetables should be promoted, there is no scientific basis for promoting 

9 them to the exclusion of other sources of vitamins C, E and the carotenoids. 

10 d) There is epidemiologic and laboratory support for particular nutrients 

1 1 Among the approximately 75 epidemiologic studies that have calculated vitamin C 

12 intake, at least three-fourths of them found vitamin C to be not only in the protective 

13 direction, but statistically significantly so. This is in spite of extraordinary problems of 

14 measurement and analysis. Similarly, a large proportion of studies that have calculated beta- 

15 carotene intake have found statistically significant protection. 

16 Finally, we mustn't forget that the laboratory data help us to interpret the 

17 epidemiologic data (and vice versa). The laboratory data are abundant that there 

18 is clearly a role for vitamin C, for vitamin E, for beta-carotene, fo» lolic acid, and 

19 for numerous other micronutrients. This role involves not just basic "vitamin" 

20 functions, but prevention of oxidative damage, improved immune functions, and 

21 other actions that reduce our risk of major chronic diseases. 

22 Appendix in presents some of the laboratory data for some of the antioxidants. 

23 There are literally hundreds of studies, supporting all of these nutrients. 

24 e) What is the right amount of each nutrient? 

25 The FDA seems to feel it needs to know a specific number of milligrams that are 

26 protective against these chronic diseases, in order to fulfill its mission rationally. This 

27 quest is misguided for several reasons. 

28 The required level is determined in part by the level of oxidant stress. Unlike 

29 nutrients whose function relates solely to a specific enzyme function, which can be 

30 saturated, antioxidants are needed in proportion to the leve! of the agent which must 

31 be defended against. Individuals, or populations, vary in the level of such stressors, 

32 which include such things as nitrosamines and radicals from smoking or alcohol, 

33 ozone level, other environmental pollutants, infections which stimulate neutrophil 

34 oxidative burst, vigorous exercise which increases oxidative damage, chronic diseases, 

35 sunlight exposure, etc. No single level will be "right" at all times in all persons. 

36 Consistent with that observation, most of the epidemiologic data suggest that 

37 there is not a threshold, but rather a continuous trend of decreasing risk with 



193 



1 increasing intake. Most studies are summarized or reported as comparisons of top 

2 with bottom quartile or other quantile, but in most cases there is indication of a 

3 continuum in between, often verified by a significant trend test. In such a situation 

4 the concept of a single "right" level is inappropriate, but such a situation is very 

5 consistent with a statement that, for example, a diet high in antioxidants may help 

6 reduce risk of some cancers. 

7 The effective level may well differ for different diseases or cancer sites. An 

8 amount which affords a minimally adequate risk reduction with regard to stomach 

9 cancer may be insufficient to provide detectable risk reduction for lung cancer. In this 

10 case, a search for the "right" level stems from a medical treatment model rather than a 

11 prevention model. 

12 Most epidemiologic data seem to suggest that at least within the ranges detectable in 

13 epidemiologic studies, there is a continuum, and "more is better". The question then 

14 becomes, 1) what are the ranges seen in epidemiologic studies? Or more broadly, what is the 

15 actual range of normal intake? and 2) is there an upper limit beyond which more js harmful? 

16 * What is the range of normal intake? 

17 Much of FDA regulating revolves around the RDA levels, assuming that they ■ 

18 represent "the" normal level, and the only scientifically justified level. However, the Food 

19 and Nutrition Board (FNB) explicitly states that the RDAs do not represent "optimum" 

20 intakes. Furthermore, RDA levels are frequently based on the amount necessary to produce a 

21 gradual reversal of acute deficiency syndromes, and not on any long-term health criterion. 

22 The FNB acknowledges that "Data on the role of diet as a causal or contributing factor in 

23 chronic and degenerative disease lead to recommendations derived through approaches 

24 different from those used in developing RDAs...." (1989 RDA book, p. 20) That is, possible 

25 needs relating to cancer, heart disease or other chronic diseases explicitly have not entered 

26 into consideration in setting the RDAs. 

27 What is "normal" or "desirable" intake? Several sources give us a clue. 

28 * For comparison, RDA levels 

29 vitamin C, 60 mg 

30 vitamin E, 8 tocopherol equivalents (TE) per day (F) 

31 folic acid, 180 micrograms (F) 

32 * Paleolithic diets: Investigators have studied modem primitive peoples, and have attempted 

33 to reconstruct the diets of paleolithic humans. Their estimate of average vitamin C 

34 intake: 290 mg/dav. 

35 * Amounts that would be provided in diet recommendations issued jointly by the U.S. 

36 Department of Agriculture and the Department of Health and Human Services. If 

37 those recommendations, such as the National Cancer Institute's "Five a day" campaign 



194 



1 were followed, an appropriate diet would contain 800-1000 RE of beta-carotene, 250- 

2 500 me of vitamin C. 15-18 TE of vitamin E. and 300-400 ug folic acid. 

3 * Amounts that are consumed in the U.S. by people eating three fruits and three vegetables 

4 a day, in the NHANES II data: 248 mg vitamin C. 

5 * Primate ancestors? If 1,000 calories (of our typical 2,000-3,000) were obtained from leafy 

6 greens (as is true of primates), that would provide between 300 mg and 1.500 mg of 

7 vitamin C. and 4,000-8,000 micrograms of folic acid . 

8 * Amounts found to be protective in epidemiologic studies. Howe et al. conducted a meta- 

9 analysis of 12 breast cancer studies in various countries: "If all postmenopausal 

10 women in the population were to increase fruit and vegetable intakes to reach an 

1 1 average daily consumption of vitamin C totaling 380 mg/day ..., risk of breast cancer in 

12 the population of postmenopausal women in North American would be reduced by 

13 16%." 

14 The point here is that the RDA levels are not appropriate to use as a standard for what 

15 diets should contain. Almost certainly, we evolved on and should be getting, for optimum 

16 health, amounts much higher than those minimum levels. 



17 IL HOW ADEQUATE ARE TYPICAL AMERICAN DIETS NOW? 

18 It is often asserted that micronutriem intake in the U.S. is ample. This is based on 

19 three assumptions: 1) that most Americans eat a reasonably good, well-balanced diet; 2) that 

20 the RDA levels indicate "ample", which is probably not the case as noted above; 3) that 

21 average intakes tell the story adequately. 

22 Do we eat a good, well-balanced diet? NO! Studies using national datasets have 

23 shown that on any given day, 40% of Americans don't have even one serving of fruit or fruit 

24 juice; only about one-third of us have even one serving of a fruit or vegetable rich in vitamin 

25 C or carotenes. Twenty percent have no servings of fruit or fruit juice in four days. 

26 Average vitamin C intakes are about 100 mg/day for adults. However, it is important 

27 to remember that an average is dragged up by people at the extremes, namely the relatively 

28 few people with high intakes. For most nutrients the median is a better representation of 

29 central tendency, that intake for which half the population has a lower and half a higher 

30 intake. The medians tell quite a different story. For vitamin C, the median intake among 

31 males is 73 mg, and 66 mg among females. For vitamin E, the median intake is 7.3 ATE for 

32 males and 5.4 ATE for females. Among those below 131% of poverty, the median among 

33 American women (CSFTI) is about 50 mg vitamin C (that is, 50% of the population has levels 

34 below the RDA), and only 4 ATE vitamin E. 

35 When we consider the distribution of intakes, it becomes clear that substantial 



195 



1 segments of the population routinely consume considerably less than the RDA, for each of 

2 these nutrients. Table 1 shows the estimated 25th and 10th percentile of intake of antioxidant 

3 nutrients. USDA survey data based on four days of diet data reveal that 25% of the sample 

4 consumed an average of only 39 mg/day of vitamin C and 4. 1 ATE of vitamin E, over four 

5 nonconsecurive days. And 10% of the sample consumed only 25 mg vitamin C and 3 ATE 

6 vitamin E. 

Biochemical measures reveal that many in U.S. have inadequate antioxidant nutrient 

8 status, even with respect to our current understanding of what might be inadequate. For 

9 vitamin C, nationally representative data exist for serum levels, in the NHANES II serum 

10 data. Like the dietary intake data, the mean levels of approximately 0.9 mg/dl in adults 

1 1 would seem to indicate that levels are adequate. Once again, however, consideration of the 

12 distribution rather than the mean reveals that substantial segments of the population have 

13 levels that most vitamin C experts would agree are low levels. As shown in table 2, 

14 approximately 10-15% of white males and 20-30% of African American males have serum 

15 ascorbic acid levels of 0.3 mg/dl or less. In human experimental studies, 0.3 mg/day is 

16 approximately the level attained after one month on about 10 mg/day of vitamin C It is a 

17 level which, if maintained for an extended period, might result in some frank symptoms of 

18 scurvy, and is very likely to result in the symptoms just prior to frank scurvy, such as fatigue 

19 and irritability. 

20 Thus, the biochemical data that exist from nationally representative samples reveal that 

21 as many as one-fourth to one-third of black males have extremely low serum ascorbic acid 

22 levels. While the story is worse for those near the poverty level than for those who are well 

23 off, it is important to be clear that major segments of Americans at every level have very low 

24 intakes of fruits and vegetables, and therefore very low micronutrient intakes. 

25 m. WHAT ABOUT SUPPLEMENT USE? 

26 Contrary to popular belief, we are not all supplementing our diets regularly. About 

27 one-fourth of Americans takes a dietary supplement daily. The vast majority of those take a 

28 multiple vitamin. In 1987, about 17% took a multiple vitamin daily, 8% took vitamin C and 

29 4% took vitamin E on a daily basis. The proportions among older people and among white 

30 and well-educated people are somewhat higher. Furthermore, among blacks daily 

31 consumption is much less common, the comparable figures being 15.9% for daily use of any 

32 supplement, 4.5% for vitamin C and 2.4% for vitamin E. Thus, among the overwhelming 

33 majority of blacks and low-income persons, supplement use is a trivial source of intake of 

34 these nutrients. 

35 Thus, most people still take no vitamins regularly, and relatively few take anything 

36 other than one-a-day types. But are vitamins being taken excessively? The 95th percentile 

37 level was 600 mg of vitamin C (only somewhat above what one could get on NCI's 5-a-day 

38 diet); and 5,945 IU vitamin A (only somewhat above the RDA of 5,000.) 



196 



1 A serious concern of the FDA and some others concerned about encouraging or 

2 permitting vitamin supplementation is that people may take vitamins and neglect to obtain a 

3 good well-balanced diet, or may neglect to seek proper medical care. There is simply no 

4 evidence to support either of these fears. Quite the contrary. 

5 * Several studies have examined the diets of supplement users and nonusers. Almost 

6 without exception, they have found that supplement users have better diets. They eat 

7 more fruits and vegetables, and less fat. People take supplements because they feel it 

8 improves their health, and they take other steps consistent with that goal. Supplement 

9 users drink less, smoke less, and are leaner. Psychologically, it is a truism that 

10 healthy behaviors reinforce one another. 

11 * Furthermore, to assume that people will take supplements instead of seeking medical 

12 attention is simply to slander the intelligence of the American people. People know 

13 that when you have a symptom of something serious, you go to a doctor. People 

14 really are smart enough to know that a vitamin pill is not going to cure cancer. Any 

15 other assertion is just silly. 

16 IV. WHAT ABOUT TOXIC LEVELS? 

17 Time doesn't permit a full discussion of toxicity. Anything, even water, is toxic at 

18 some level. The goal of government is not and should not be to totally prevent the possibility 

19 of hazard. If it were, we would ban salt, sugar, alcohol and tobacco straight away. The first 

20 two are by far the major additives to the American diet, probably deleteriously so. But the 

21 proper role of government is to educate people as to their proper uses and potential effects. 

22 For most vitamins, the range of safe use is very wide, in the thousands of milligrams 

23 of vitamin C, hundreds or even thousands of tocopherol equivalents of vitamin E. For those 

24 two nutrients, and some others such as beta-carotene, it is not even really clear that any likely 

25 level will cause more than transient indicator symptoms such as loose bowels or skin 

26 yellowing. We know of some nutrients that do indeed have toxicities, mostly at very high 

27 levels (e.g., 50,000 units of vitamin A) consumed for long periods of time. 

28 I believe it should be the role of the FDA to provide for the informing of the public 

29 about the data on potential toxicity, but also on the data on potential benefit In a democracy, 

30 people should have the ability to make informed judgments, and not rely on an overburdened 

31 and understaffed agency to make decisions for them. 

32 V. THE EVIDENCE IS INCREASING EXPLOSIVELY 

33 A key point here is the rapidity with which the evidence is growing. There are 

34 literally hundreds of scientific articles on the role of oxidation in disease, and the role of 

35 antioxidants in preventing it, published every month. There seems to be a large international 

36 conference on antioxidants and health about every month. 



197 



1 Consider just the epidemiologic data, and just in one area, the role of antioxidant 

2 nutrients or their food sources in reducing cancer risk. In 1982 the National Academy of 

3 Sciences published their report, "Diet, Nurrition and Cancer". Since that year, 175 

4 epidemiologic studies have been published on antioxidant nutrients and their food sources and 

5 cancer risk ! In 1989 the Surgeon General's Diet and Health report was published. Since that 

6 year, 75 epidemiologic studies on the antioxidant/cancer link have been published. And this 

7 is completely without mentioning the thousands of biochemical and other laboratory studies, 

8 or the epidemiologic studies on other diseases. 

9 The point here is that what we thought we knew five or ten years ago is not what we 

10 know now. And surely the same will be said five or ten or 50 years in the future. What we 

1 1 know about the health role of the molecules we call nutrients is a tiny fraction of what there 

12 is to know. Any opinion formed as little as five years ago is already out of date. The 

13 overwhelming majority of the evidence that is emerging is that these nutrients are vastly more 

14 important in promoting health than we dreamed until recently, and that the levels that may be 

15 beneficial are larger than most people dreamed until recently. 

16 Thus, this explosion of evidence of a beneficial role should be a major warning that 

17 we must not restrict access to these things on the basis of 

18 * outdated information about benefits and functions 

19 * outmoded notions of what are normal levels = 

20 * incorrect assumptions about the adequacy of current intake 

21 * incorrect assumptions about probability of risk from supplement use 

22 * anecdotal case reports about occasional adverse reactions or contamination 

23 * moralistic judgments about where people should be getting their nutrients, or about 

24 which types of manufacturers should be allowed to make a profit on what they 

25 sell 

26 VI. PUBLIC POLICY AND FDA'S ROLE 

27 Given the rapidity of the expansion of evidence on a beneficial role for numerous 

28 micronutrients, and given the arguments and data presented above, I suggest that FDA's 

29 money and efforts could be refocussed. I believe my comments here apply to a wide range of 

30 products, not just vitamins. 

31 1) I do not believe that it is proper for FDA to impede the sale of substances simply 

32 because it does not agree with the claims for it Our knowledge is far too minimal. Probable 

33 beneficial effects are continually being discovered. Many cannot ever be thoroughly tested 

34 because of the high costs and limited opportunities for such research. That does not mean 

35 that such benefits may not in fact be true. Aspirin was initially an "herb". Digitalis is a plant 

36 product. Tamoxifen, the potential anticancer agent the NCI is currently excited about, is 

37 made from a bush. Why should one suppose that no further similar discoveries will be 

38 made? But they will not all be tested in placebo-controlled randomized ffials; I believe the 

39 public should have the right to try for themselves to see if they experience benefit 



10 



198 



1 2) I do believe FDA can and should play a very useful role in ensuring content, 

2 quality and potency . A consumer has a right to expect that a 500 mg tablet of vitamin C 

3 contains vitamin C, in 500 mg, in an absorbable form, and uncontaminated with harmful 

4 substances. This is what consumers expect of FDA and assume it is doing, but in fact is not. 

5 For herbs, where such content and potency issues are more difficult, I do not believe FDA 

6 should take them off the market simply because they cannot be specified to the same 

7 precision as vitamins. Rather, labeling as explicit as possible should be encouraged, telling 

8 the name of the herb, etc. 

9 3) I do believe FDA could play a very useful role as an informational agency . FDA 

10 could perhaps maintain an up-to-date bibliography of research on both the benefits and risks 

11 of the substances in question. It would include all available data, not simply those papers that 

12 FDA agrees with or believes meet some criteria. This bibliography would then be made 

13 available to scientists, or to consumers who wish to investigate the issue. 

14 4) I believe the FDA has an appropriate role in safety, but I do not believe this should 

15 include powers to remove substances from the market unless there is a large, substantial, clear 

16 and present danger to substantial segments of the population. (Alcohol, salt, sugar, aspirin, 

17 tobacco, and any number of other things are on the market. For any one of these individually 

18 there is vastly more evidence of potential risks to vastly larger segments of the population.) I 

19 do not believe the role should include policing health claims, unless they are equivalent to 

20 crying "Fire" in a crowded room, such as "This will cure cancer by itself." (Even then, I 

21 believe people are sensible enough to know better.) I do not believe the role should include 

22 demanding unrealistically extensive and expensive clinical trials that would have the effect of 

23 removing products from the market. 

24 I do believe that it is appropriate for FDA to warn consumers if there is evidence of 

25 adverse side effects, or if the substance is conrraindicated for some people. Such warnings 

26 could go right on the label. Ideally, in conjunction with item 3 above, the label might say 

27 where to write or call for a bibliography of all existing data on risks and benefits of the 

28 substance. 

29 Given the compelling evidence supporting the biochemical mechanisms of many of 

30 these nutrients, the extensive and consistent epidemiologic data suggesting health benefits, the 

31 low intakes of large segments of the population, and the complete imbalance of the magnitude 

32 of potential benefits compared with potential hazards, I suggest that FDA's efforts might 

33 appropriately be directed toward assuring content and providing information on these 

34 substances. 



11 



199 





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200 



Table 2 
Low Ser-JS Ascarbate Levels by Age, Sex and Race, 
NKANZS II, 1976-30 



Per:srt of Population at or below 0.3 ac/dL 
white Slack 

Ace Male ?eaale Mala regal; 

25-44 14.7 3.5 17.9 12-2 

45-54 15-5 6.S 25.7 9.7 

55-74 11.4 4.6 27.3 4.1 



201 



1 Appendix I - Are clinical trials the answer? 

2 The FDA and others have repeatedly suggested that the epidemiologic data are not enough, 

3 and that complete clarity must await the conduct and completion of clinical trials. This 

4 assumption is contrary to accepted opinion (see below), and has perhaps clouded the 

5 reviewers' judgment about the epidemiologic evidence. For cancer, particularly specific 

6 cancer sites, controlled clinical trials are impractical, as noted by the Proposed Rulemaking on 

7 Lipids and Cancer 

8 "Intervention studies of cancer are difficult to perform because the rarity of 

9 outcome for specific types of cancer requires enormous sample sizes. In addition, 

10 the long latency, 20 to 30 years for most types of cancer, makes such studies 

11 difficult and costly. For this reason, observational epidemiology studies are 

12 generally accepted as sufficient, as was the case for the first Surgeon General's 

13 Report on Smoking." (Lipid/Cancer Rule, FR 60773) 

1 4 The assumption that ongoing or proposed controlled clinical trials will settle the question is 

15 incorrect for several reasons. In the following discussion, in sections a) and b), we will 

16 reference every clinical trial involving vitamin C, vitamin E or beta-carotene, conducted or 

17 funded by the National Cancer Institute, which covers most such trials in the United States 

18 and indeed in the world. 

19 a) Because of the rarity of most cancers, most clinical trials are conducted in special, high- 

20 risk populations, usually with precancerous conditions. 

21 Berman, CA: Women with cervical dysplasia 

22 Greenberg, NY: Persons with previous colon adenomas 

23 Greenberg, NY: Persons with previous basal cell skin ca. 

24 Hong, TX: Leukoplakia, previous head/neck cancer 

25 Luande,Tanzania: Albinos 

26 McLarty, TX: Men exposed to asbestos 

27 Omenn, WA: Men exposed to asbestos 

28 Mobarhan, IL: Previous colon cancer 

29 Romney, NY: Women with cervical dysplasia 

30 NCI/China: Esophageal dysplasia 

31 When such studies are concluded: 

32 If the agents are not effective, the question will remain unanswered of whether or not 

33 they might have been effective in persons in whom the disease had not 

34 progressed so far. These preventive agents presumably act in part by 

35 preventing initiation (e.g., blocking nitrosation). 

36 If the agents are effective, the doubt will remain as to whether they would indeed be 

37 effective in persons without that condition. Successfully treating a 

38 precancerous condition is not the same as preventing even that condition. 

39 Moreover, treating or preventing the progression of a precancerous condition is 

14 



202 



l 

2 
3 



not the same as preventing cancer, because a) not all colon polyps, e.g., will go 
on to become cancer, and b) cancer may arise through other biologic pathways 
than the one being treated.. 



4 
5 
6 
7 
8 
9 



That such studies will be of doubtful use to the FDA in deciding on a health claim in 
the general population is attested by the current situation of folic acid and neural tube 
defects. In that case, an agent was shown to be effective in preventing neural tube 
defects in a clinical trial in women with a previous child with this defect Yet both 
the FDA and the CDC are currendy reluctant to generalize this to the general 
population. 



10 b) Because of the large numbers of subjects involved, most studies will test one or at most a 

1 1 small number of different agents and dose levels, and in only certain cancers. 



12 
13 
14 
15 
16 
17 
18 



Single agents 
P.I. 

Berman, CA: 
Luande, Tanzania 
Mobarhan, IL 
Romney, NY 
Hennekens, MA 



Endpoint 
Cervical ca 
Skin ca 
Colon prolif 
Cervic dysplas 
Any cancer 



Agent, dose 
beta-car, 30 mg . 
beta-car, 100 mg 
beta-car, 30 mg 
beta-car, 30 mg 
beta-car, 50 mg QOD 



19 
20 

21 
22 
23 
24 
25 
26 
27 
28 
29 
30 

31 
32 
33 
34 
35 



Two agents singly &/or factorial 



Balmes, CA 
Cullen, CN 
Goodman, WA 
Keogh, MD 
Meyskens, CA 
Valanis, CA 
McLarty, TX 
Omenn, WA 
Buring, MA 
NCI/Finland 
NCI/China 



lung ca 
(CARET) 



Lung (asbestosis) 

Lung 

Lung 

Lung 

Esophagus 



Several agents in combination 

NCI/China Esophagus 

NCI/China Esophagus 

Greenberg, NC Colon polyps 



beta-car, 30 mg 
retinol 25,000 IU 



beta-car 50 mg, retinol, 25,000 
beta-car 30 mg, retinol 25,000/d 
beta-car 50 mg QOD, vit E 600 
beta-car 20 mg, vit E, 50 mg 
vit C, 120 mg, Molybdenum 30 ug 



beta-car 25 mg, vit E 20 mg, Se 50 
Multiple vit. tablet 
beta-car 30 mg, vit C 1000 mg, 
vit E, 400 mg 



36 From these studies we will leam about 

37 1) For cervical cancer the effect of beta-carotene at 30 mg/day; no information on role of 

38 ascorbic acid, consistendy protective in epidemiologic studies. For progression of 



15 



203 



1 cervical dysplasia, the effect of beta-carotene at 30 mg/day. 

2 2) For colonic cell proliferation in persons with previous colon cancer, the effect of beta- 

3 carotene at 30 mg/day. For development of new colon polyps in persons with 

4 previous ones, the effect of 30 mg beta-carotene, 1000 mg vitamin C and 400 mg 

5 vitamin E in various combinations. 

6 3) For esophageal cancer in Chinese with esophageal dysplasia, the effect of a multiple 

vitamin supplement In a general Chinese high-risk population, the effect of 

8 combinations of either 120 mg vitamin C plus 30 ug molybdenum, or 25 mg beta- 

9 carotene plus 20 mg vitamin E plus 50 ug selenium. 

10 4) For lung cancer in men exposed to asbestos, the effect of 30 mg or more of beta- 

1 1 carotene. In heavy smokers or a more general population, the effect of beta-carotene 

12 at 20 mg or more, or of vitamin E at 50 mg or 300 mg, or combinations. 

13 A few studies now planned or ongoing are in a general population with reasonably large 

14 numbers (Hennekens, Buring, NCVFinland, NCI/China). They will eventually provide 

15 information regarding the major cancers such as lung, colon and breast. Information on less 

16 frequent cancers such as cervix, pancreas and rectum will take many years and wiU still be 

17 based on relatively small numbers. As noted above, an average of ten years of follow-up in 

18 over 11,000 persons produced only 27 cases of pancreatic cancer in the HANES I Follow-Up. 

19 A two-arm study totaling 22,000 persons for ten years might still produce only 27 cases in 

20 each arm, treatment and control. Even colon and rectum combined (which may have different 

21 etiologies with respect to micronutrients) attained only 56 cases among males and females 

22 combined, in the HANES I Follow-Up. Supposing one had 27 or even 56 cases in the 

23 placebo arm, and fewer in the treatment arm if there were a treatment effect, those numbers 

24 would be large enough only to detect a very large treatment effect Essentially no cancers of 

25 the oral cavity, esophagus and stomach will turn up in populations of American white 

26 physicians and nurses. Those cancers are rapidly fatal, and their incidence is much higher in 

27 blacks than whites, and evidence for a role for antioxidants is srrong. 

28 Studies with a single agent provide information at only one dose level. Studies with 

29 combinations of agents, such as the combination arm of some factorial studies, provide 

30 information about the combined effect of two agents/doses. If the latter proves effective, the 

31 FDA will still be in the position of not knowing which agent was effective, a process which 

32 would then take further decades. If a single agent proves effective (against one of the major 

33 cancers), further studies would then have to be done to determine whether other dose levels 

34 were effective, and whether combinations with other agents could produce or increase 

35 effectiveness. 

36 None of the studies above (with the exception of Greenberg/polyps, if that is a factorial 

37 design) will provide any information about possible effectiveness of vitamin C. This is 

38 despite virtually unanimous epidemiologic studies indicating a strong preventive role in 

39 cancers of the esophagus, oral cavity and stomach, and strong evidence for a role in cancer of 

40 the cervix, pancreas and lung. None will provide any information about vitamin E except 

41 with regard to lung cancer. 

16 



204 



1 The studies above are extremely important and valuable. They will indeed provide definitive 

2 information about the relatively limited questions they are asking, about the role of single 

3 agents at single high doses against major cancers or in precancerous conditions. None of the 

4 studies will provide any evidence at all aoout the effectiveness of dose levels at a range 

5 attainable in a normal diet. Thus, even if they are successful in the limited questions they are 

6 asking, they will provide no information to address the question relevant to the proposed 

7 rulemaking . 

8 c) Some critically important and relevant questions cannot be addressed by clinical trials 

9 There are a number of questions which no remotely feasible clinical trial can answer. 

10 Chief among these is the effect of long duration of treatment -- i.e., lifetime -- and the related 

1 1 question of whether effective treatment must start in childhood. A number of proposed 

12 mechanisms involve prevention of initiation — prevention of oxidative damage to the genome 

13 or prevention of the formation or activation of carcinogens like nirrosamines. It is likely that 

14 with regard to these mechanisms, an adequate level of antioxidants is required from childhood 

15 on. Another important question which is questionably feasible involves interactions among 

16 nutrients. For example, no clinical trial proposes to test vitamin E except at very high doses, 

17 yet a number of studies have found statistically significant reduced cancer risk at high dietary 

18 levels. It is possible that high dietary levels of vitamin E, when supported by high dietary 

19 levels of vitamin C (which reconstitutes oxidized E), are indeed protective. To test this 

20 adequately would require numerous combinations of moderate doses, and larger sample size 

21 and duration because overall significant treatment effects might be less than seen at higher 

22 doses. Yet, a moderate risk reduction would be of great importance when applied to a whole 

23 population. 

24 These are crucial questions, which are not testable by clinical trials, and to which only 

25 epidemiology provides answers. 



17 



205 



1 Appendix II: Reservations about epidemiologic data 

2 Why don't we see 100% consistency in epidemiologic results? 

3 Absence of 100% agreement in epidemiologic results for a single nutrient doesn't 

4 invalidate conclusions about that nutrient, let alone that class of nutrients. 

5 Often in examining a group of epidemiologic studies about a given antioxidant in a 

6 specific type of cancer, one will see, for example, five studies with statistically significantly 

7 protective findings, and one with no association or no statistically significant association. (It 

8 is important to note that for most cancer sites which have been studied for these nutrients, 

9 this is in fact the kind of ratio of significant to nonsignificant studies that has been seen.) 

10 Even if the ratio were 4:2, or even 3:3, do such exceptions mean that the relationship is 

1 1 suspect? Before reaching such a conclusion, it is necessary to consider the reasons for such 

12 findings. Some of the major reasons will be described briefly here. 

13 The nature of the diet questionnaire used is the most common reason for discrepant 

14 findings. Epidemiologists have, particularly in the past, used instruments which were 

15 incapable or poorly capable of assessing all of the nutrients of interest. Of 31 studies of 

16 antioxidant nutrients or their food sources and lung cancer, the overwhelming majority weTe _z 

17 designed to assess beta-carotene, and were not designed to nor capable of adequately -y^ 

18 assessing vitamin C or vitamin E. That is, they did not include on the food list foods rich in *53r 

19 those nutrients. Only about 10 of the 31 studies even reported on vitamin C. Of those that 

20 did, a few of them explicitly state in the discussion that their instrument could not do a good 

21 job of assessing vitamin C. For vitamin E the situation is even worse, as scientists focused 

22 on studying beta-carotene have typically included no foods which are good sources of that 

23 vitamin. The importance of negative findings under such circumstances should be questioned. 

24 In a related reason for discrepant findings, most studies in developed countries have 

25 failed to include nutrient intake from fortified sources. Thus, even when food sources of 

26 vitamin C such as citrus fruits may be included, fortified cereals often are not included, thus 

27 introducing misclassification of the respondent's actual intake of vitamin C and vitamin E, 

28 two vitamins for which fortified foods represent important sources. 

29 Similarly, most studies have either omitted vitamin supplement intake altogether or 

30 have treated it poorly in the analysis. For example, the only dietary study that failed to find 

31 vitamin C to be associated with significantly reduced risk of cervical cancer studied a group 

32 of American white women in the 1980s and failed to include supplement use. Since perhaps 

33 30% of this group use vitamin supplements daily, many who were placed in the lower three 

34 quartiles based on diet alone would have been placed in the upper quartile if their supplement 

35 intake had been included. The resulting dietary estimates may bear no relationship to blood 

36 levels of the nutrient, and have extensive misclassification, resulting in poor or no ability to 

37 detect a real association. This situation, far from being rare, is actually the rule in most 

38 epidemiologic studies. For beta-carotene, only recently introduced into vitamin supplements 

18 



206 



1 and still consumed very rarely, this is not a problem. For vitamin C and vitamin E, the 

2 problem is severe, in studies conducted in the United States or in many developed countries. 

3 Even among studies that asked about and used vitamin supplement information, the 

4 analytic approach was often incorrect. Most that have done it at all have simply included 

5 supplement use as a binary variable in the statistical model, but have reported on the 

6 association of the dietary variable. In nonusers of supplements, this might be fine; in users of 

7 supplements, however, this amounts to trying to detect an effect of "low" intake when many 

8 of those with "low" intake from foods may in fact have high total intake, from diet plus 

9 supplements. 

10 Another methodologic problem which can lead to failure to find an association is lack 

11 of dispersion of the nutrient variable in the population, a problem widely recognized by those 

12 studying the effects of fat intake. If most persons in a population are low (or high) in intake 

13 of a particular nutrient, it will be difficult or impossible to detect an effect of high (or low) 

14 intake. It is conceivable that uniformly high intake may have been the case in some 

15 Canadian or Hawaiian studies that have found only weak or inconsistent effects of antioxidant 

16 micronutrients. On the other hand, the problem of uniformly low intake is clearly the case in 

17 a number of studies in high-risk areas of developing countries. Li et al. found no effect of 

18 fruit intake on esophageal cancer, unlike the overwhelming majority of other studies; but the 

19 high intake category in that study was 35 times per year . Notani et al. found no effect of 

20 fruit in esophageal cancer, but in that study fruit intake was so infrequent that the high intake 

21 category consisted of those who ate it once a week. (This was in contrast to vegetables, 

22 where the high intake category was once a day, and where a protective effect was indeed 

23 found.) 

24 This observation reveals an important reason why one or another specific antioxidant 

25 may appear to be unimportant in a particular population: populations vary in their food 

26 sources. Some populations rarely eat fruit, because it is unavailable or expensive. In such 
populations, carotenoids or vitamin E may provide most of the antioxidant function. 

28 Conversely, in some populations carrots or other rich sources of beta-carotene are eaten 

29 rarely. In such populations the antioxidant function may be provided chiefly by other 

30 antioxidants. 

31 Thus, any approach which examines the antioxidant nutrients separately will find 

32 instances in which a particular nutrient did not appear statistically significandy protective in 

33 that particular population or with that particular dietary instrument The observation which 

34 should sway the FDA, however, is the overwhelming consistency of the epidemiologic 

35 evidence for antioxidant nutrients in general. Even looking within a single nutrient, 33 of 46 

36 studies that calculated vitamin C intake have found statistically significant protective effects, 

37 and essentially all the rest were in the protective direction. With a broader view, for the 

38 class of nutrients called antioxidants, of approximately 180 studies that examined either 

39 vitamin C or beta-carotene or vitamin E or their rich food sources in cancers of the 

40 lung, larynx, esophagus, oral cavity, pancreas, stomach, cervix, rectum, colon, ovary, 

19 



207 



1 endometrium, breast, bladder, about 160 have found statistically significantly reduced 

2 risk. 

3 The FDA review of the evidence regarding dietary fat and cancer faced similar 

4 uncertainties regarding specific types of fat That proposed ruling on health claims for fat 

5 noted that "the effects of different types of fat... have not been studied extensively, and the 

6 results that do bear on this issue are as yet inconclusive." (Fat/cancer proposed rule) 

7 Elsewhere that proposed rule notes that "the biochemical mechanism by which fats affect 

8 tumorigenesis has not been definitely established", and "there was no dose-response study that 

9 quantitatively delineated the level of fat reduction in the diet necessary to cause reduced 

10 tumorigenesis". Furthermore, a reading of the FDA summary of the animal and 

1 1 epidemiologic evidence regarding fat and cancer reveals statements on almost every page that 

12 state that "results are not in complete agreement", "inconsistent results", " most of the case- 

13 control studies found a significant association" (6 of 13), "results of these two prospective 

14 studies are contradictory", etc. Nevertheless, that proposed ruling concludes, correctly in our 

15 view, that "repeated and consistent findings of an association between certain dietary factors 

16 and diseases are likely to be real and indicative of a cause-and-effect relationship." 

17 Many agree that the evidence for a protective effect of fruits and vegetables is strong, 

18 but are uncomfortable extending that to support for particular nutrient effects 

19 The reluctance is usually based on two grounds: the association could be due to other T. 

20 factors associated with fruit/vegetable intake, and even if the protective factor is an 

21 antioxidant, we can't tell which nutrient is effective. 

22 a) "The association could be due to other factors." 

23 Note first that every other dietary factor fails by the same catch- 22 noted above. You 

24 can't prove it is fiber because it might be antioxidants. ... 

25 First, it might be the fiber. Biologic rationales can always be constructed, but we have 

26 to stretch pretty far for biologic rationales for a relationship between fiber and cancer 

27 of the lung, larynx, pancreas and other sites with strong fruit/vegetable evidence; and 

28 while we're making that stretch for a biologic rationale, we have to at the same time 

29 dismiss the incontrovertible laboratory data on free radical and oxidative damage. 

30 Second, it might be an inverse relationship with fat or meat intake. But again, 

31 1) we have to stretch for a biologic rationale for some sites; 

32 2) supporting studies are found in countries where this inverse relationship is weak 

33 or nonexistent Studies have been conducted in about 30 countries, many of 

34 which do not have our constellation of correlated behaviors to which the 

35 association could be attributed. In less developed countries, for example, a diet 

36 low in fruit is not associated with high meat or fat intake, but with rice or 

37 another starchy staple. 

20 



208 



1 3) the few studies that have looked have found reduced risk with high fruit/vegetable 

2 intake even within strata of high fat/meat intake; 

3 4) in the U.S., cross-sectionally, those with a high vegetable intake do not in fact 

4 have a lower fat intake (ref Patterson & Block.) 

5 Third, it could be other components of fruit and vegetables, such as folic acid. 

6 Indeed, it is likely that folic acid is important for at least some cancer sites. But given 
the biochemical data on the role of oxidative and free-radical events in carcinogenesis, 

8 it seems unreasonable to postulate that it is folic acid (or another candidate) instead of 

9 antioxidants, that antioxidants really have no role. One can believe that other 

10 components may well be important, while still believing that an antioxidant function is 

1 1 probably an important factor in some of these cancer sites. 

12 Finally, it could be non-dietary factors positively or negatively associated with 

13 consumption of foods rich in beta-carotene or vitamin C, such as smoking. But again, 

14 supporting studies arc found in countries lacking our cluster of behaviors; and, 

15 numerous studies have found protection from these factors even within strata of 

16 smokers or non-smokers. 

17 b) "Even if the protective factor is an antioxidant, we can't tell which nutrient is effective." 

18 The reasons why it is inappropriate to consider the epidemiologic data separately 

19 • nutrient by nutrient have been discussed already. The biochemistry also makes such a 

20 separate consideration inappropriate. The nutrients under consideration are all 

21 antioxidants; the association of oxidation with cancer is unquestioned; these nutrients 

22 reinforce and substitute for one another in biological systems; the evidence for each of 

23 them separately in animal and in vitro systems is strong. The evidence is strong from 

24 laboratory and epidemiologic data that each of these nutrients has a role in one or 

25 another cancer site. It would be ludicrous to fail to acknowledge the probable role of 

26 vitamin C in helping to reduce the risk of stomach or esophageal cancer, for example. 

27 (In those sites a combined total of 15 out of 15 studies that calculated vitamin C 

28 intake (not just fruit) found statistically significant risk reduction.) And it would be 

29 equally ludicrous to fail to acknowledge the probable role of carotene in helping to 

30 reduce the risk of lung cancer. While the epidemiologic evidence regarding vitamin E 

31 is less voluminous (because most questionnaires have not calculated vitamin E), its 

32 unquestioned role as a lipid antioxidant, the laboratory and animal data supporting its 

33 anticarcinogenic activity, and the epidemiologic data regarding a role in lung cancer 

34 should be enough to support a statement that this antioxidant, like others, may help 

35 reduce the risk of some cancers. 



21 



209 



1 Appendix IK: Extensive laboratory data support a role for vitamin C, vitamin E, 

2 carotenoids, numerous other micronutrients. 

3 I. The biochemical data are strong, and" could stand alone in support of an association 

4 between antioxidants and cancer. 

5 The carcinogenic role of oxidative processes and free radicals is widely supported. 

6 There is substantial scientific agreement that such processes play a role in both 

7 initiation and promotion, for a variety of cancers. 

8 Antioxidants and free-radical scavengers block these processes. Vitamin C, vitamin E 

9 and beta-carotene perform these functions. It seems almost a logical truism that 

10 therefore these agents have a role in preventing carcinogenesis and promotion. 

1 1 Antioxidants and free-radical scavenging. The evidence for a role for free radicals in 

12 carcinogenesis is very strong [21]. Humans are exposed to a sea of oxidative and radical 

13 agents producing damage to lipids, proteins, membranes and DNA. The sources are both 

14 external (substances resulting from cooking of food; polluted air, cigarette smoke; background 

15 radiation; ozone) and internal (normal energy metabolism; normal function of white blood 

16 cells in killing invading organisms). Without continuous and abundant antioxidant and 

17 radical-scavenging capability, survival would be impossible. - 

18 Vitamins C and E have been shown to protect against radical-mediated damage to cell 

19 membranes, fats and DNA, and beta-carotene has been shown to block highly reactive 

20 oxygen. 

21 II. Laboratory animal data support a preventive role for antioxidants 

22 Numerous studies have shown an antitumorigenic role of antioxidant vitamins in 

23 animal models. While an effect is not seen for every nutrient in every animal model 

24 and dosage regimen, the data quite consistently show a strong and significant effect 

25 Only a few such studies are noted here. 

26 The administration of ascorbic acid was found to inhibit the development of 

27 metaplastic and neoplastic lesions of the respiratory tract of mice exposed to fiberglass 

28 dust [31], and of rats exposed to plutonium dioxide particles [32], and to protect 

29 against abnormal growth and malignant transformation of hamster lung cultures that 

30 were subjected repeatedly to cigarette smoke [33]. Sodium ascorbate, fed ad libitum 

31 in the diet, completely prevented 1,2-dimethylhydrazine-induced colon tumors in the 

32 rad, and reduced DMH-induced kidney tumors [34]. Pretreatment with vitamin C 

33 reduced estradiol-induced renal tumors by 50% [28]. Beta-carotene reduced by two- 

34 thirds the yield of gastric carcinomas induced in rats by N-methyl-N'-nitro-N- 

35 nitrosoguanidine [35]. 



22 



210 



Mr. Towns. Dr. Rosenberg. 



STATEMENT OF IRWIN H. ROSENBERG, PROFESSOR OF 
MEDICINE AND NUTRITION, TUFTS UNIVERSITY 

Dr. Rosenberg. Mr. Chairman, members of the subcommittee, I 
am a professor of medicine and nutrition at Tufts University where 
my primary scientific interest is to understand the utilization of vi- 
tamins ana the way in which vitamins in our diet participate in the 
maintenance of our health and the prevention of disabling degen- 
erative diseases. I have spent my career with an interest in this. 

Our own research, and that of others, has produced hopeful stud- 
ies in adults and older Americans showing that certain vitamins 
are associated with decreasing risks of some major degenerative 
diseases. These observations give promise. We must convey the 
message that proper dietary choice will contribute to promotion of 
health and longevity and reduce the burden of disease. That is the 
challenge before this committee, before the Federal Government, 
and before the American people. 

There must be ways in which the supplements are made fully 
available to American consumers but that availability also includes 
the responsibility for providing the information that permits 
healthful choice and thereby promotes both the physical and eco- 
nomic health of the Nation. There must be governmental oversight 
mechanisms to protect these choices and to contribute to maximal 
health and safety. No nutrient or other substance is safe at any 
dose. 

While there is a great range of safety of various nutrients, in 
general, the mineral nutrients are more toxic at higher doses than 
vitamins and more susceptible to detrimental interactions when 
doses are out of balance. 

Such interactions have been observed between zinc and copper. 
High doses of zinc can be toxic and can contribute to copper defi- 
ciency. And iron and calcium, which can interfere with intestinal 
absorption of one other. 

Genetic or age differences make doses of iron somewhat dan- 
gerous for some individuals while the same amounts may be safe 
for others. 

We have heard that iron pills are the leading cause of poisoning 
in children. There are also some interactions among vitamins such 
as folate and vitamin B-12 which makes high doses of folic acid 
dangerous for some elderly. But this is not a perfect world where 
everyone has a nutritionally trained health counselor. 

How do we convey this to the public? My position on this is the 
same as that endorsed by the American Society for Clinical Nutri- 
tion and the American Institute of Nutrition, the two societies that 
represent the majority of active clinical nutrition scientists and nu- 
trition scientists in this country. 

That position is as follows: There should be no special difference 
between regulation of disease-specific claims in labels of conven- 
tional foods and labeling of dietary supplements by the Food and 
Drug Administration. We believe that the FDA has adopted a re- 
sponsible position in utilizing, as a standard, general agreement 
among the scientific community as the standard necessary for sup- 
port of disease-specific health claims on food. The FDA procedure 



211 

would ensure that health claims are reliable and protect consumers 
from fraudulent health claims and increase the credibility of claims 
that are made. 

If more and more consumers come to rely on dietary supplements 
by their choice to protect and promote their health, it is all the 
more important that health claims and supplement labeling be reli- 
able. Our consumers must have the protection and oversight of the 
Food and Drug Administration in such matters. Such safety issues 
must not be left to the marketplace, in my view. 

As a chairman of the scientific panel to review over-the-counter 
vitamins and minerals that reported in 1979 to the FDA and as 
former chair of the food and nutrition board of the National Acad- 
emy of Sciences, I am particularly distressed to see the current 
campaign of misinformation that I also experienced previously as 
a panel chairman. 

There are claims currently that charge erroneously that the Nu- 
trition Labeling and Education Act allows the FDA to ban the sale 
of many types of supplement products, that, in fact, the FDA will 
take people's vitamins away. 

Others have claimed that the FDA regulations implementing the 
NLEA will require consumers to acquire a prescription for purchas- 
ing a dietary supplement. These inaccurate claims were made be- 
fore. They were wrong in my days on that panel, and they are 
wrong now. I don't believe the FDA has the authority, nor do I 
even expect they have the interest, in removing access, appropriate 
access to vitamins and minerals. 

The NLEA empowers the FDA to regulate claims on dietary sup- 
plement labels. In that case, some of the pending legislation — and 
in this H.R. 1709, would remove supervisory power of the Food and 
Drug Administration over dietary supplements, and I think that 
would be bad for the American consumer, for American food pro- 
ducers, for the food industry, and for the pharmaceutical industry. 

We must be sure, in closing, to use that information available 
wisely to give maximal health and safety to the public. And in that 
sense, the proposed FDA regulations appear to be on a prudent 
course. 

Mr. Towns. Dr. Rosenberg, the red light is on. Thank you very 
much. 

[The prepared statement of Dr. Rosenberg follows:] 



212 

TESTIMONY 

BY 

IRWIN H. ROSENBERG. M.D. 
PROFESSOR OF MEDICINE AND NUTRITION 

AT 

TUFTS UNIVERSITY 



THE HOUSE GOVERNMENT OPERATIONS SUBCOMMITTEE 
ON HUMAN RESOURCES AND INTERGOVERNMENTAL RELATIONS 



HEARING ON 



FDA's REGULATION OF DIETARY SUPPLEMENTS 



JULY 20, 1993 



213 



Mr. Chairman, I am grateful tor this opportunity to appear before this 
subcommittee for this hearing on a topic of great importance to the health and well 
being of the American people. I am a Professor of Medicine and Nutrition at Tufts 
University where my primary scientific interest is to understand the utilization of 
vitamins by the elderlv and the way in which vitamins in our diet particiDate in the 
maintenance cf health and the prevention of disabling degenerative diseases. 
Throughout my whole career I have been committed to research on vitamins in 
health ana disease with special interest in the absorption of vitamins including folic 
acid and vitamin D and their interactions with other nutrients and disease 
processes. During my career, I have watched the evolution of nutritional science as 
it progressed from a phase of our understanding of the way in which vitamins and 
minerals prevent deficiency diseases as established by the brilliant research of the 
first half of this century, much of it in the United States, to the recent and growing 
understanding of the importance of dietary vitamins and minerals in the 
maintenance of full function including the diminished risk of some of the 
important degenerative diseases. Our own research and that of others has produced 
very hopeful studies in adults and older Americans showing that higher intakes of 
certain dietary vitamins are associated with decreasing risk of some of the major 
degenerative diseases that afflict our population and cany such a huge toll in misery 
and health care expenditure, including heart disease, cancer, osteoporosis, cataract, 
and loss of immune function. These observations give promise, I believe, that the 
1990's will be known for the way in which nutrition research has led us to see diet 
and nutrition as a means for promoting vigorous health and preventing disease 
rather than the message of the 1980's which was all too often that diets were 
simplythe cause of disease. We must convey the message to the American people 
that proper dietary choice, including the appropriate nutrients will contribute to 
promotion of health and longevity and decrease the burden of disease. 

The science of nutrition has provided us with one of the great opportunities 
of the 20th century by identifying all the vitamins in our diets, making possible their 
synthesis and widespread use. We must continue to add to that scientific progress 
and also to utilize the fruits of that science wisely. That is the challenge before this 
committee, before the federal government and before the American people. No 
society in history has ever had such a plentiful/ wholesome, and inexpensive food 
supply and also wide access to vitamin and mineral supplements. We should 
continue to make these supplements available to American consumers but with 
that availability we have a responsibility of providing the information that permits 
healthful choice and thereby promotes both the physical and the economic health of 
the nation. Perhaps no moment in the history of nutrition science has offered more 
possibilities than the present which is all the more reason to reflect soberly on a 
sound national food and nutrition policy to make the best use of the emerging 
information. The truest free market exists when the consumer is given the tools to 
learn about and choose a healthful diet and to make other healthful choices. There 
must be societal mechanisms to defend those choices and to contribute to maximal 



214 



health and safetv. 



How should we get this information to consumers in an orderly way? In the 
best of all worlds- each consumer should make choices based on his or her own 
special needs and health and family history In the face of the best advice of health 
professionals including doctors, registered dietitians, and nurse practitioners. These 
trained professionals could compare special needs and benefits of diets and dietary 
supplements and avoid inadequate or excessive intakes of these foods and 
nutrients. No nutrient or other substance is sate at any dose. While there is a great 
range of safety or risk of vanous nutrients, in general the mineral nutrients are 
more toxic at higher doses that axe vitamins and more susceptible to detrimental 
interactions when doses are out of balance. Such interactions have been observed 
between zinc and copper, (high doses of zinc can be toxic and also can contribute to 
copper deficiency) and iron and calcium, which can interfere with intestinal 
absorption of one another. Genetic or age differences make doses of iron somewhat 
dangerous for some individuals while the same amounts may be safe for others. 
Iron pills are a leading cause of poisoning for children. There are also some 
interactions among vitamins such as the folate and vitamin B12 which makes high 
doses of folic acid dangerous for certain elderly, and very high doses of vitamin E 
may counteract some erfects of vitamin K. But this is not the perfect worid where 
everyone has a nutri tionally trained health counselor, therefore how do we convey 
this information to the public to allow prudent choices? 

My position on this is the same as that which has been endorsed by the 
American Society for Clinical Nutrition and the American Institute of Nutrition, 
the two societies that represent the majority of active clinical nutrition scientists and 
nutrition scientists in this country. That position is as follows: 

1) There should be no special difference between regulation of disease- 
specific claims in labeling of conventional foods and labeling of dietary 
supplements by the Food and Drug Administration. 

2) We believe that the FDA has adopted a responsible position in 
utilizing as a standard "general agreement among the scientific 
cornmunity" as the standard necessary for support of disease-specific 
health claims on foods. 

The FDA procedure would ensure that health claims are reliable and protect 
consumers from fraudulent health claims and increase the credibility of claims that 

are made. If more and more consumers come to rely on dietary supplements by 

their choice to protect and promote their health, it is all the more important that 
health claims on supplement labels be reliable. Our consumers must have the 
protection and oversight of the Food and Drug Administration. Such safety issues 
must not be left to the market place. 



215 



As a chair of a scientific panei to review over-the-counter vitamins and 
minerals that reported in 1979 to the FDA, and as former chair of the Food and 
Nutrition Board of the National Academy of Sciences, I am particularly distressed to 
see the current campaign of misinformation that I also experienced previously as a 
panel chairman. There are claims currently that charge erroneously that the 
Nutrition Labeling and Education Act allows the FDA to ban the sale of many types 
of supplement products, mat in fact the FDA will "take people's vitamins away'. 
Others nave claimed that FDA regulations implementing the NLEA will require 
consumers to acquire a prescription before purchasing a dietary supplement. These 
inaccurate claims were made before: they were wrong then and they are wrong now. 
The FDA does not have either the authority, or in my judgment, the intention, of 
removing the access to vitamins or minerals. The NLEA only empowers the FDA 
to regulate claims on food and dietary supplement labels. Some of the pending 
legislation that would remove supervisory power of the Food and Drug 
Administration over dietary supplements as distinguished from foods would be a 
serious disservice to the American consumer, to the American' food producers, the 
food industry, and the pharmaceutical industry and would potentially rum back the 
clock on 75 years of truly impressive progress in the research on the appropriate use 
and benefits of vitamins and minerals. i 

I should emphasize that most of the current research es ablish.es an 
association between the intake of certain vitamins or minerals in the diet 
sometimes with additional supplements, and a diminished ris c of certain 
degeneradve conditions including heart disease, some forms of cancer, and cataract 
The fact that there are these associations, does not prove a cause and effect 
relationship between specific nutrients in those diets and protection against disease. 
Nor do we know exactly which elements in a diet that is rich in fruits and vegetables 
and therefore in antioxidant nutrients are responsible for all the beneficial effects. 
We should not be making specific recommendations or claims, in my view, about 
specific vitamins or minerals until we have established the dose range and the 
safety of their administration and their effectiveness in preventing or ameliorating 
disease. That is a research challenge that should have the hig lest national priority 
as well 

As I indicated earlier, Mr. Chairman, nutrition science 1 as given us a great 
opportunity to move forward with health promotion, especially by the appropriate 
use of diet, including the beneficial nutrients. We must be sure to use that 
information wisely so that it gives maximal health and safety to the public and in 
that quest, the proposed FDA regulations appear to be on a prudent course and some 
of the pending legislation would be detrimental to the course of nutritional science 
and health. i 



216 



Mr. Towns. Dr. Bailey. 



STATEMENT OF LYNN B. BAILEY, PhJ)., NUTRITION PROFES- 
SOR, FOOD SCIENCE AND HUMAN NUTRITION DEPARTMENT, 
UNTVERSITY OF FLORIDA 

Dr. Bailey. Mr. Chairman, thank you for this invitation to 
present testimony today. 

My name is Lynn Bailey, and I am a nutrition professor at the 
University of Florida. For the past 15 years, I have conducted an 
active human nutrition research program in the area of folic acid 
metabolism. 

Folic acid can significantly reduce the risk of birth defects which 
affect the brain and/or spinal cord, referred to as neural tube de- 
fects. I will define folic acid and neural tube defects and focus on 
the following two topics: No. 1, data supportive of the folic acid/ 
neural tube defect health claim; and, No. 2, implementation of the 
public health service recommendation. 

Folic acid is a water soluble vitamin required by the body for 
cells to divide and to produce vital protein components, for exam- 
ple, amino acids. 

The neural tube is a fetal tissue that develops into the spinal 
cord and the brain. Defects in the development of the neural tube 
occur within the first 28 days following conception. A landmark 
study illustrating data supporting a health claim is the rigorously 
controlled folic acid intervention study. Folic acid supplementation 
alone at a 4 milligram per day level reduced the risk of neural tube 
defects by 72 percent. 

There was no evidence that vitamins other than folic acid had 
any effect on risk reduction, nor did they enhance the protective ef- 
fect of folic acid. The important conclusion from this study was that 
folic acid alone significantly reduced the risk of recurrent neural 
tube defects. 

The questions of risk reduction in women with no history of neu- 
ral tube defects were addressed in a Hungarian intervention study 
involving more than 4,000 women. There were no neural tube de- 
fect occurrences in the group receiving .8 milligrams of folic acid 
as a component of a multivitamin supplement compared to six neu- 
ral tube defects in the groups not receiving folic acid. 

In addition to these nighly controlled intervention studies, there 
have been a number of observational studies in the United States 
in which a significant reduction in risk for occurrence of neural 
tube defects has been associated with a folic acid intake of .4 milli- 
grams per day as a component of a multivitamin supplement. 

In the past decade alone, there have been 10 major studies ad- 
dressing this question. The percent reduction in risk for neural 
tube defects associated with folic acid intake, with one exception, 
ranged from 60 to 100 percent. It is clear that scientific evidence 
supports the 1992 Public Health Service recommendation that all 
women of child bearing age consume .4 milligrams of folic acid per 
day to reduce the risk of neural tube defects. This recommendation 
is, in fact, the health claim supported by a strong scientific data 
base and the scientific community. 

My second topic is that of implementation of this recommenda- 
tion. The majority of pregnancies in the United States are un- 



217 

planned. The neural tube develops and the defect occurs before 
most women even know they are pregnant. Therefore, it is impera- 
tive to ensure adequate daily folic acid intake through the repro- 
ductive period which spans 30 years. 

This group includes 60 to 70 million women in the U.S. popu- 
lation. Options for implementation of the recommendation are cur- 
rently being considered by the FDA. The first option is improve- 
ment of the dietary habits. The public health recommendation to 
consume .4 milligrams is based on this amount in supplements in 
addition to diet. 

Dietary folate is not utilized as efficiently as supplemental folic 
acid. Consumption of the recommended amount from diet alone is 
not likely based on typical U.S. dietary patterns. Concentrated die- 
tary sources of folate including green leafy vegetables are infre- 
quently consumed. 

The second point, on supplementation: The potential for 60 mil- 
lion women to take a supplement for 30 years is not great. At-risk 
women in lower socioeconomic groups would be hard to reach. 

Related to supplementation, the safety issue the FDA has been 
carefully considering, is the potential for high doses of supple- 
mental folic acid to interfere with the diagnosis of a vitamin B-12 
deficiency. The scientific data do not support the conclusion that 
levels below 1 milligram per day are of a concern in this regard. 
Supplemental folic acid is clearly associated with a reduction in 
risk of neural tube defects. How can we translate these findings to 
ensure adequate intake if supplementation is not a viable option? 
The option of choice appears to be fortification of flour, which is 
likely to enhance the folic acid intake of most women in the target 
population without increasing the total population intake to levels 
above 1 milligram per day. 

In conclusion, folic acid reduces the risk of neural tube defects. 
Scientific data strongly support a health claim and fortification of 
flour appears to be the best approach to implement the Public 
Health Service recommendation. 

Thank you. 

Mr. Towns. Thank you Dr. Bailey. 

[The prepared statement of Dr. Bailey follows:] 



218 



TESTIMONY - FDA'S REGULATION OP DIETARY SUPPLEMENTS 

Lynn B. Bailey, Ph.D. 
Professor 

Thank you for the invitation to present this testimony today. 
My name is Lynn Bailey, and I am a professor of human nutrition in 
the Food Science and Human Nutrition Department at the University 
of Florida. For the past 15 years, I have conducted an active 
research program in the area of folic acid metabolism, 
bioavailability, requirement determination, and status assessment. 
Today I will critique scientific data that support the Public 
Health Service recommendation related to folic acid and neural tube 
defects and the health claim that folic acid will reduce the risk 
of having an infant with a neural tube defect. 

My testimony will address the following: 

I. Descriptive Background 

A. Folic Acid 

B. Neural Tube Defects 

a. Spina bifida 

b. Anencephaly 

c. Health care costs 

II. Critique of Scie ntific Data Supporting Neural Tube Defect 
Risk Reduction 

III. Public Health Service Rec« ™?^^ff^ ion 

IV. Folic Acid/Neural Tube Defect Health Claim Approval 

V. I"P 1 TT« r |tation of Public Health Service Recommendation 

A. Improving Dietary Habits 

B. Fortification of Flour 

C. Supplementation 

VI. Plenary Supplement Regulation 



I. Descriptive Background 

A. Folic Acid 

Folic acid is a water soluble vitamin that cannot be 
synthesized by the body. It is concentrated in selected food 
sources including green leafy vegetables, citrus fruit, whole grain 
cereals, and legumes. This vitamin is required by the body for 
cells to divide and to produce amino acids, the building blocks of 
proteins. When insufficient amounts are consumed, cells do not 
divide properly, tissue growth is slowed down, and the utilization 



219 



of cellular components is impaired. The requirement for this 
vitamin increases dramatically during periods of rapid growth. 

B. Neural Tube Defects 

a. S pina bifida 

The neural tube is embryonic tissue that forms the brain and 
spinal chord of the developing fetus. This tissue develops and 
closes during the first 28 days following conception. When the 
lower portion of the neural tube fails to develop and close, the 
spinal nerves protrude through an opening in the tube resulting in 
severe nerve damage. Paralysis and loss of bowel and bladder 
control are associated with this condition referred to as spina 
bifida. This type of birth defect is a major contributor to 
serious developmental disabilities in the U.S.. 

b. Anencephaly 

Anencephaly is a defect that affects the upper portion of the 
neural tube that forms the brain. Infants with this defect are 
usually stillborn or die shortly after birth. 

Spina bifida and anencephaly account for - 90% of neural tube 
defects. The estimated number of neural tube defect-affected 
births in the U.S. is -2,500 per year. However, this is an 
underestimate since this number does not include affected 
pregnancies that are terminated following prenatal diagnosis. 

c. Health Care Costs 

The public health impact of spina bifida in the U.S. is 
substantial: the annual medical and surgical costs (based on 1985 
dollars) for persons with spina bifida exceed $200 million (MMWR, 
1992) . The lifetime cost of medical intervention and institutional 
care is enormous and continues to increase due to an increase in 
life expectancy. In addition to the financial burden of health 
care costs and lost ability to earn an income; the affected 
families undergo severe psychological trauma. 

The focus of my presentation today is on folic acid which we 
now know will reduce the risk of neural tube defects. It is 
important to realize that the risk of neural tube defects is 
influenced by a number of factors in addition to folic acid. These 
factors include genetics, geographical location, and race. For 
example, women with a family history of neural tube defects are at 
a much higher risk of having a baby with this type of birth defect . 



2 - 



220 



II. Scientific Data - Folic Acid/Neural Tube Defect Risk 
Reduction 

The potential association between dietary factors and the 
development of neural tube defects has been recognized for many 
years. Scientists began a decade ago to aggressively investigate 
the role of folic acid as a causative factor in the development of 
these defect because of its role in cell division and tissue 
development. Data from these earlier studies served as the 
"springboard" for more recent well designed protocols. These early 
studies carried out by investigators including Smithells and 
Laurence resulted in the suggestion that "poor diet" increased the 
risk of neural tube defects and that supplemental folic acid was 
associated with risk reduction. 

The critical period of protection for prevention of neural 
tube defects is the first 28 days of gestation when the neural tube 
forms and closes. Research studies designed to determine which 
factors are "protective", evaluate the periconceptional period 
which includes a period of time shortly before conception through 
the "critical period" one month after conception. Scientists have 
used different research approaches to investigate the potential 
protective effect of folic acid including observational studies, 
non randomized intervention trials, and randomized controlled 
intervention trials. 

Several of the earlier studies by Smithells were non 
randomized intervention trials in which women taking folic acid 
containing multivitamins were compared with women not taking 
supplements. The conclusion from these studies was that the risk of 
neural tube defect "recurrence" was significantly reduced by 
consumption of multivitamins containing - 0.4 mg of folic acid 
during the periconceptional period. Conclusions from these studies 
were tentative due to specific aspects of the research protocols 
including the following: (a) the treatments were not randomly 
assigned which potentially biased the interpretation (women who do 
not take supplements may be quite different from women who do) ; 
(b) subjects involved in these studies were women who had 
previously had an infant with a neural tube defect and were at 
higher risk for "recurrence"; and (c) since folic acid was only one 
component of the multivitamin mixture it was not possible to 
separate out the potential influence of the nutrients. 

Laurence conducted a small study in which women were 
randomly assigned to take a supplement containing only folic acid 
or a placebo. This study was important because the treatments were 
randomly assigned to the subjects, thus eliminating the potential 
for bias. This study focused specifically on the potential role of 
folic acid in reducing the risk of having a neural tube defect - 
affected pregnancy. The data were "suggestive" that folic acid 



221 



reduced the risk of neural tube defect recurrence. The level of 
folic acid supplementation used was 10 fold higher (4 mg/d) than 
that evaluated by Smithells. 

These and other early studies laid the groundwork for the 
recent "landmark" study conducted by the British Medical Research 
Council (MRC) . The MRC study (1991) was a well designed randomly 
controlled intervention trial in which folic acid treatment alone 
was compared with the following: folic acid plus other vitamins and 
minerals; other vitamins and minerals alone; and a placebo. Folic 
acid supplementation reduced the risk for neural tube defect 
"recurrence" by 72%. There was no evidence that vitamins other 
than folic acid had any effect on risk reduction, nor did they 
enhance the protective effect of folic acid. The magnitude of the 
folic acid protection was so great that the study was stopped prior 
to the projected completion date. The important conclusion from 
this study was that folic acid alone, when taken during the 
periconceptional period, significantly reduces the risk of neural 
tube defects. These data also provided evidence that not all 
neural tube defects are responsive to folic acid since there were 
some recurrences in the folic acid treatment groups. The fact that 
the level of supplementation was 4 mg/d did not answer the question 
of protection at lower doses commonly available in supplements (0.4 
- . 8 mg/d) . It also raised the concern that this level of 
supplementation may have some potential unknown negative effect 
since it is 10 times the current Recommended Dietary Allowance 
(RDA) for folic acid for the pregnant woman. This study, in 
addition to all preceding studies evaluated risk reduction for 
neural tube defect "recurrence". Since 95% of all babies are born 
to mothers with no history of neural tube defect -affected 
pregnancies; it was important to establish whether folic acid 
reduces the risk of first time "occurrence" of neural tube defects. 

The key questions of protection with lower doses and risk 
reduction in the general population were addressed in a Hungarian 
randomized controlled intervention trial (1992) involving more than 
4000 women with no prior neural tube defect history. The level of 
folic acid was 0.8 mg/d and was provided as one component of a 
multivitamin supplement. This supplement resulted in 100% 
protection whereas there were 6 occurrences of neural tube -defected 
affected pregnancies in the group receiving the placebo supplement. 
In addition, the number of other congenital anomalies was 50% lower 
in the folic acid multivitamin group. This was the second large 
scale intervention study that was terminated prematurely due to the 
magnitude of protection afforded by folic acid and folic acid 
containing multivitamins. The first study showed that a large dose 
of folic acid only reduced the risk of recurrence of neural tube 
defects, whereas this second study showed that a multivitamin 
supplement containing a lower dose of folic acid reduced the risk 
of occurrence of neural defects. 



- 4 - 



222 



In addition to these intervention studies, there have been a 
number of observational studies in the U.S. in which the reduction 
in the risk for neural tube defects has been associated with folic 
acid intake. With the exception of one study, a significant 
protective effect of folic acid containing multivitamins was 
observed. One such study was that of Milunsky and coworkers who 
obtained information regarding vitamin use during the 
periconceptional period from -22,000 pregnant women. The data 
relative to vitamin supplementation was collected before a 
diagnosis of a neural tube defect and was obtained during pregnancy 
thus minimizing recall bias. A significant reduction in risk was 
observed for women who took multivitamins containing folic acid 
compared to women who either took multivitamins without folic acid 
or no vitamin supplements. The risk of having a baby with a neural 
tube defect was no different in women who took multivitamins 
without folic acid compared to those who did not take supplements. 
Data from this study also illustrated the importance of 
supplementation during early gestation, since folic acid 
supplementation that began after this period provided no 
protection. 

Recently, Werler and coworkers (1993) reported data from a 
case controlled study in Boston, Philadelphia, and Toronto in which 
occurrent risk reduction was evaluated in women taking daily 
multivitamins containing predominately 0.4 mg of folic acid. These 
workers observed a 60% reduction in risk of occurrent neural tube 
defects in the group taking multivitamins containing folic acid. 
For subjects who did not take supplements, the effect of dietary 
folic acid intake was estimated based on computer analysis of food 
frequency consumption data. There was a significant dose related 
decline in risk according to quintile of folate intake. The 
conclusions based on the dietary intake data confirm those of a 
group of Australian scientists (Bower and Stanley) who also found 
a significant protective effect of higher dietary folate intake. 
The observation by Werler that the risk of neural tube defects was 
reduced by 60% in the group consuming multivitamins containing 0.4 
mg/d of folic acid confirmed the findings observed in other non 
intervention studies in the U.S. as well as the intervention trials 
in other countries . 

The table below summarizes data from the majority of both 
intervention and observational studies published in the last 
decade. The percent reduction in risk for neural tube defects 
associated with folic acid intake with one exception ranged from 60 
- 100%. 



223 



NEURAL TUBE DEFECT RISK REDUCTION - FOLIC ACID CONSUMPTION 
Study Percent Risk Reduction 



Intervention 

Smithells (1983) 86 

Lawrence (1981) 60 

MRC (1991) 72 

Vergel (1992) 100 

Czeizel (1992) 100 

Observational 

Mulinaire (1988) 60 

Mills (1989) 

Milunsky (1989) 72 

Bower (1989) 75 

Werler (1993) 60 



III. Public Health Service Recommendation 

It is clear that scientific evidence does support the 1992 
recommendation of the Public Health Service (PHS) which is as 
follows: 

"All women of childbearing age in the United States who are 
capable of becoming pregnant should consume 0.4 mg of folic acid 
per day for the purpose of reducing their risk of having a 
pregnancy affected with spina bifida or other neural tube defects. 
Because the effects of higher intakes are not well known but 
include complicating the diagnosis of vitamin B 12 deficiency, care 
should be taken to keep total folate consumption at <1 mg per day, 
except under the supervision of a physician. Women who have had a 
prior neural tube defect -affected pregnancy are at high risk of 
having a subsequent affected pregnancy. When these women are 
planning to become pregnant, they should consult their physicians 
for advice." (MMWR, 1992) 

This recommendation is in fact a health claim and one that is 
substantiated by a large body of scientific evidence. Prior to the 
decision to release this recommendation, an advisory panel of 
expert scientists including myself met at the Centers for Disease 
Control (CDC) (July 1992) to carefully consider whether the data 
substantiated such a recommendation. There was unanimous agreement 
among panel members that the scientific data were clearly 
supportive. 



6 - 



224 



IV. Polic Acid/Neural Tube Defect Health Claim Approval 

Following the release of the PHS recommendation, FDA 
appointed a Folic Acid Subcommittee of FDA's Food Advisory 
Committee (Dr. Rosenberg and I are members) . There was agreement 
by this subcommittee, during the November, 1992 meeting that the 
PHS recommendation should be supported and methods for 
implementation of the policy carefully considered. Data related to 
potential toxicity issues were reviewed and unresolved issues 
discussed. After reviewing the data related to potential risks 
versus the potential benefit: I voted in favor of a health claim. 
The fact that the Folic Acid Subcommittee supported the PHS 
recommendation in essence was a vote in support of a health claim. 
A number of committee members however voiced concerns regarding the 
health claim. At the second meeting of the Folic Acid Subcommittee 
held in April, 1993, the majority of committee members voted in 
favor of a health claim. FDA has reversed its previous decision 
and has approved a health claim relative to folic acid and neural 
tube defects based on the scientific data and current consensus of 
scientists on this issue. 

VI. Implementation of PES Recommendation 

The magnitude of potential benefit from implementation of 
this recommendation was estimated by CDC to be a 50% reduction in 
the annual number of affected cases. A position statement written 
by the Food & Nutrition Science Alliance representing the American 
Dietetic Association, the American Institute of Nutrition, the 
American Society of Clinical Nutrition, and the Institute of Food 
Technologists emphasizes that implementation of this recommendation 
"is an important opportunity to improve public health and reduce 
health costs" . 

FDA and other government agencies are currently evaluating 
three alternatives to determine the safest and most effective way 
to reduce the risk of neural tube defects without causing harm to 
those not in the target population. The options for implementation 
of the PHS recommendation include the following: 

A. Im proving Dietary Habits: 

The recommended intake of 0.4 mg/d of folic acid is 
approximately twice the current RDA for women of child bearing age 

(180 fig/d) . A review of new data relative to the RDA for folate 
resulted in the conclusion that the RDA needs to be increased 

(Bailey, June 1993: National Academy of Symposium "Should the 
Recommended Dietary Allowances Be Revised?"). An increase in the 
RDA would bring the PHS recommendation in line with recommendations 
for dietary folic acid for the general population. 

The PHS recommendation to consume 0.4 mg/d was based on the 
amount contained in the majority of su pplements taken in addition 



225 



to diet . It is important to note that dietary "folate" is actually 
a more complex chemical form of the vitamin and is not as available 
to the body as folic acid, which is the form provided in 
supplements and fortified foods. Dietary folate must be converted 
by the body to a less complex structure (i.e. folic acid) and this 
mechanism is not 100% efficient. 

Since dose response studies have not been conducted, it is 
unknown whether levels below 0.4 mg/d would provide a comparable 
risk reduction. To consume the known "protective level" of dietary 
folic acid, the average dietary consumption in the U.S. would have 
to increase dramatically representing a substantial change in 
typical U.S. dietary patterns. Dietary folic acid can potentially 
be increased significantly by following the guidelines of the USDA 
Food Guide Pyramid which recommends that people eat 2-4 servings of 
fruit, 3-5 servings of vegetables, and 6-11 servings of grain 
products per day. Increasing consumption of folic acid-rich foods 
such as green leafy vegetables, citrus fruit, legumes, and whole 
grains is consistent with current national nutrition guidelines 
designed to reduce the risks of chronic diseases. Although the 
estimated dietary folate intake in the U.S. for adult women (-200 
jig/d) is considered to be an underestimate; it is clear that 
concentrated sources of dietary folate are not frequently consumed 
by the population ( National Health and Nutrition Examination 
Survey II) . 

B. Fortification of Flour with Folic Acid 

The Folic Acid Subcommittee of FDA supports fortification of 
flour coupled with nutrition education strategies as the most 
appropriate options to implement the PHS recommendation. 
Fortification of flour is likely to enhance the folic acid intake 
of most women in the target population without subjecting other 
population subgroups to excessive intakes of this nutrient. The 
majority of pregnancies in the U.S. are unplanned and the neural 
tube develops before most women even know they are pregnant . For 
these reasons, it is imperative to ensure an adequate daily folate 
intake throughout the reproductive period which spans approximately 
30 years (ages 14 - 45) . The levels of fortification being 
considered are moderate (restoration to pre-milling level or 2 
times restoration) . The recommendation to restore folic acid to 
the restoration level originated 20 years ago when the National 
Academy of Sciences developed a position paper on "Proposed 
Fortification Policy for Cereal -Grain Products" (NAS: 1974) . 

C. Su pplements 

The amount of folic acid in the majority of multivitamin 
preparations available over the counter is 0.4 mg which is the US 
RDA. Implementation of the PHS policy should incorporate 
supplementation when appropriate for the population subgroup at 

- 8 - 



226 



risk. For example, supplemental folic acid is currently being 
distributed to women of reproductive age in the Brownsville Texas 
area where the incidence of neural tube defects is very high 
compared to the national average. 

Use of an approved health claim by the food industry should 
facilitate a change in folic acid consumption habits for both folic 
acid-dense foods and dietary supplements in the targeted "at risk" 
population subgroup. A statement related to the maximum safe level 
of intake will be an important educational component of the 
approved claim. 

The PHS recommendation relates only to the 60-70 million women 
of reproductive age. It is anticipated however that intake of 
folic acid will increase in all segments of the population and 
specific safety concerns should be monitored with appropriate 
surveillance mechanisms. Of concern is the potential for large 
doses of supplemental folic acid (1-10 mg/d) to interfere with the 
diagnosis of vitamin B, 2 deficiency. The primary potential adverse 
effect is the "masking" of anemia in clinical vitamin B 12 
deficiency that can delay diagnosis and appropriate treatment and 
result in irreversible neurologic damage. In addition, there is 
new evidence that subclinical vitamin B 12 deficiency may be more 
common than previously assumed (Lindenbaum) . It is clear that we 
need to evaluate vitamin B, 2 status in national surveys such as 
NHANES III using a battery of biochemical indices and to monitor 
changes in status in relation to folic acid intake. Another 
potential safety issues related to excessive folic acid intake is 
interaction with specific drug therapies; however, published data 
do not support this concern. Data were insufficient related to any 
of these safety issues to prevent the approval of a folic 
acid/neural tube defect health claim, however, these safety 
concerns should be monitored in response to increases in intake. 

VII. Dietary Supplement Regulations 

I support FDA's position that there should be no special 
differences between regulation of disease specific claims in 
labeling of conventional foods as contrasted with labeling of 
dietary supplements. I concur with the current FDA position 
regarding the approval process for health claims for dietary 
supplements (Fed Reg: 6/18/93) . Regulatory control of supplement 
labeling is essential to minimize the risk of over dosages. This is 
illustrated by the potential risk of very high doses of 
supplemental folic acid to interfere with the diagnosis of a 
vitamin B l2 deficiency. It is extremely important that the role of 
the specific food or supplement labeled with the health claim be 
considered in the context of the total diet. 

Thank you again for the opportunity to present this testimony 
today. 

- 9 - 



227 



SELECTED REFERENCES 

Mulinare J, JF Codero, JD Erickson and RJ Berry. Periconceptional 
use of multivitamins and the occurrence of neural tube defects. 
JAMA 1988 260:3141-3145. 

Milunsky A, H Jick, SS Jick, CL Bruell, DS MacLaughlin, et al . 
Multivitamin/folic acid supplementation in early pregnancy reduces 
the prevalence of neural tube defects. JAMA 1989 262:2847-2852. 

Bower C and FJ Stanley. Dietary folate as a risk factor for neural 
tube defects: evidence from a case- control study in western 
Australia. Med J Aust 1989 150:613-619. 

Werler MM, S Shapiro, and A Mitchell. Periconceptional folic acid 
exposure and risk of occurrent neural tube defects. JAMA 1993 
269:1257-1261. 

Wald N et al. Prevention of neural tube defects: results of the 
Medical Research Council vitamin study. Lancet 1991 338:131-137. 

Czeizel A and I Dudas . Prevention of the first occurrence of 
neural -tube defects by periconceptional vitamin supplementation. N 
Engl J Med 1992;327:1832-5. 

Centers for Disease Control. Recommendations for the use of folic 
acid to reduce the number of cases of spina bifida and other neural 
tube defects. MMWR 1992 41:1-7. 

Bailey L. Evaluation of a new Recommended Dietary Allowance for 
folate. J Am Diet Assoc 1992 92:463-471. 

Lindenbaum J, DG Savage, Stabler SP, and RH Allen. Diagnosis of 
cobalamin deficiency: II Relative sensitivities of serum cobalamin, 
methylmalonic acid, and total homocysteine concentrations. Am J Hem 
1990 34:99-107. 



10 



228 

Mr. Towns. Dr. Sternberg. 

STATEMENT OF ESTHER M. STERNBERG, M.D., CHIEF, UNIT ON 
NEUROENDOCRINE IMMUNOLOGY AND BEHAVIOR, CLINI- 
CAL NEUROENDOCRINOLOGY BRANCH, NATIONAL INSTI- 
TUTE OF MENTAL HEALTH, NATIONAL INSTITUTES OF 
HEALTH 

Dr. Sternberg. Thank you, Mr. Chairman, for giving me the op- 
portunity to testify today. 

I am Dr. Esther Sternberg, the chief of the Unit of 
Neuroendocrine Immunology and Behavior at the National Insti- 
tute of Mental Health. 

The last time I testified before this committee, 2 years ago, the 
hearings were directed at FDA's regulation of the dietary supple- 
ment L-tryptophan. 

Since the outbreak of the L-tryptophan EMS epidemic, 2 years 
have elapsed. The late Congressman Ted Weiss' opening statement 
read: "Millions of Americans have used the supplement L-trypto- 
phan to treat a variety of medical conditions. These consumers 
were led to believe that L-tryptophan was safe, and they were mis- 
led. This is a tragedy that should never have happened.' 

Across the United States, in the summer of 1989, 1,500 to 5,000 
people who ingested L-tryptophan became ill with a deadly crip- 
pling disease. Since I last testified, at least 6 more deaths have 
been attributed to this syndrome, with a total of 37 deaths. Be- 
cause of widespread scarring throughout the body, 60 percent of 
surviving patients are left with chronic pain, crippled, with difficul- 
ties breathing, and life threatening heart arrhythmias. 

At the 1991 hearing, I was asked, what do we do to prevent this 
from happening again? It is striking to me now that I am once 
again before this subcommittee, not to answer that question but to 
answer the opposite question. That is, should we make food supple- 
ments, of which L-tryptophan was classed as a member, more 
available, in order to provide the public with greater freedom of 
choice. 

You have asked me to update the committee on the results of our 
research into the causes of EMS in order to determine the safety 
of such a move. Two things have now become apparent. Not only 
is impure L-tryptophan capable of causing the full-blown syndrome, 
but in rodents pure L-tryptophan alone can cause severe scarring 
in some organs. 

It also has been long known that L-tryptophan in tablet form, 
but not as a component of foods, has significant dose-related effects 
on brain chemicals. 

In this context, L-tryptophan associated with EMS represents a 
product which falls under three categories of risks, that is: produc- 
tion standards related risks associated with impurities; toxic ef- 
fects, such as scarring of the pancreas; dose-related effects related 
to the natural biological effects of the chemical. 

L-tryptophan also illustrates the fact that a single product can 
pose multiple risks. There is virtually no product to which we are 
exposed which is completely risk-free. In order to judge whether a 
product is worth taking and whether it is worth taking the risks, 
one must weigh the risks versus the benefits. 



229 

And to do that, one must have detailed chemical knowledge of 
the product. Knowledge like that is derived from a range of stand- 
ards of testing which lie on a continuum, from testimonial reports 
to full-scale studies using multiple methodologies. 

Since our goal should be to predict, to the best of our abilities, 
the product's risks and prevent them, the closer one approaches 
full testing, the closer one will be to achieving the desired goals of 
predicting efficacy and providing safety. 

Where to draw the line on this continuum and whether or not 
to market a product before or after it has been fully tested is a dif- 
ficult ethical dilemma. One must balance the cost and time in- 
volved in such testing against the cost in terms of human life, if 
inadequate product testing results in toxicity and death. 

The L-tryptophan EMS epidemic can be viewed as a case study 
in the multidisciplinary analysis of causes of disease after an envi- 
ronmental exposure has occurred. It is an example that such asso- 
ciations can go unnoticed. And, therefore, history of safe use is — 
although a possible first step, it is not sufficient proof of safety. 

But in our increasingly technologically based society, people feel 
that the care of their own bodies is outside the realm of their con- 
trol. They feel that the use of dietary supplements is one way to 
exercise control over their health. 

It is tempting to assume, as did the L-tryptophan patients, that 
natural is safe and that use of natural products for treatment of 
medical conditions gives people greater control over their own 
health. 

In fact, absence of knowledge of the chemical nature of a product, 
of its risks, and the quantities to which one is exposed, actually 
gives the consumer less control over their own health than if they 
were ingesting a well-defined product. Only knowledge can guaran- 
tee safety. Only knowledge can guarantee true control. And only 
knowledge can guarantee freedom of choice. 

The occurrence of the L-tryptophan epidemic most vividly dem- 
onstrates the false sense of security provided by the assumption 
that natural is safe. 

I hope that the next time that I testify before this committee it 
will not be to, once again, address another future epidemic. I hope 
that you will not again be asking how do we prevent such tragedies 
from happening, because uninformed choice is not freedom, particu- 
larly if that choice carries with it the risk of death. 

Mr. Towns. Thank you very much. 

[The prepared statement of Dr. Sternberg follows:] 



230 




DEPARTMENT OF HEALTH & HUMAN SERVICES 



Public Health Service 



National Institutes ot Health 
Bethesda, Maryland 20892 



STATEMENT 

BY 

ESTHER M. STERNBERG, M.D. 



CHIEF 

UNIT ON NEUROENDOCRINE IMMUNOLOGY AND BEHAVIOR 

CLINICAL NEUROENDOCRINOLOGY BRANCH 

NATIONAL INSTITUTE OF MENTAL HEALTH 

NATIONAL INSTITUTES OF HEALTH 

BETHESDA, M.D. 



BEFORE THE 

SUBCOMMITTEE ON INTERGOVERNMENTAL RELATIONS 
AND HUMAN RESOURCES 

COMMITTEE ON GOVERNMENT OPERATIONS 

UNITED STATES HOUSE OF REPRESENTATIVES 



JULY 20, 1993 



231 



The L-tryptophan Eosinophilia Myalgia Syndrome (EMS): Update on 
Causes of the Syndrome and Implications for Safety of Food 
Supplements. 

L-tryptophan EMS epidemic: description and update of patients' condition: 

L-tryptophan is a naturally occurring amino acid that can be manufactured synthetically, and 
was sold as an over-the-counter food supplement for conditions including insomnia, depression, 
and premenstrual syndrome, as well as to facilitate body building by increasing muscle mass. In 
its natural form in foods, L-tryptophan occurs as a part of protein, and not as the free form which 
was sold in tablets, capsules and powders as a food supplement. The L-tryptophan eosinophilia 
myalgia syndrome (L-tryptophan EMS) was a deadly, crippling inflammatory disease which 
occurred in epidemic proportions across the United States in 1989 in persons ingesting the amino 
acid L-tryptophan. The illness affected approximately 1500 to an estimated 5000 people across the 
United States. At least 37 deaths have been definitively attributed to L-tryptophan EMS to date, 
with a calculated mortality rate of approximately 2.5%. Cases occurred in every state in the United 
States, and shewed a preponderance in Western states coinciding with the prevalence of L- 
tryptophan consumption. 

Approximately 80% of patients report some improvement in symptoms since the worst part of 
their illness, but only 10% have completely recovered. Over 60% of patients have remained 
crippled with a painful, chronic disease that has left their skin, joints and internal organs scarred 
and has interfered with their ability to carry on productive iives. Scarring of the lungs has left many 
patients with difficulty breathing, some requiring oxygen. Scarring of the electrical system in the 
heart has been associated with palpitations (irregular heart beat) and death. Permanent nerve 
damage has been reported in 65% of patients, causing chronic pain, impaired walking, and 
compromised function of the hands. Patients also complain of memory loss. Scarring around the 
muscles, skin and joints has resulted in a crippling difficulty in moving fingers, shoulders, elbows 
and other joints, and severe muscle cramping and pain. 

Political and social repercussions of the epidemic: 

As the epidemic devastated the lives of thousands who had believed that the product they were 
taking was safe, public furor and demands for greater regulatory protection were raised {see July 
18, 1991 Hearing before the Human Resources and Intergovernmental Relations Subcommittee). 
More recently, the pendulum has swung in the opposite direction, with demands from other sectors 
for greater freedom of choice, and less regulatory controls of such products. Thus, the epidemic, 
and L-tryptophan itself, can be viewed as pivotal fulcrums in an emotional public debate on the 
dilemma of balancing safety with freedom of choice in the arena of dietary supplements and self- 
medication. The issues raised by the L-tryptophan EMS epidemic en~Dody many of the issues and 
concerns relevant to science and health today, and in this sense, the L-tryptophan EMS epidemic 
can be viewed not only from the narrow and specific point of view of the epidemic itself, but as a 
symptom of the public perceptions and public health policies which may have facilitated its 
occurrence. 

Could the L-tryptophan EMS epidemic have been prevented, and what can we 
learn from the epidemic to prevent a similar tragedy from occurring again? 

Defining the implications of the L-tryptophan EMS epidemic in an effort to prevent a similar 
occurrence in the future requires an understanding of our current knowledge of the causes of the 
epidemic, an understanding of scientific criteria and standards of proof of causation of disease, a 
knowledge of the categories of risks associated with food supplements, as well as an 
understanding of the reasons behind the increased public demands for these products. Summarized 
below are our most recent findings regarding the causes of the L-tryptophan epidemic, the effects 
of pure and impure L-tryptophan in animals, and the implications these smdies have for the safety 
of this and related classes of products. Also addressed are scientific criteria for standards of proof, 
and some possible reasons for the public need for such products. 



232 



Results of scientific studies: 

(1) Taken together, animal, in vitro, epidemiological and chemical studies 
strongly indicate that: 

1. Specific lots of impure L-tryptophan, produced by a single company, Showa Denko K.K., 
appear to be an important factor in causing the L-tryptophan EMS epidemic; 

2. Several changes were made simultaneously in the production of these lots: the genetically 
engineered strain of bacteria used in the production process and several steps in the purification 
process were modified. 

3. These specific lots were found to contain over 60 different impurities. 

4. One of these impurities, 1,1-ethylidenebis [L-tryptophan], (EBT), is biologically active, 
and alone appears to have contributed to causing some but not all the features of the syndrome. 

5. Pure L-tryptophan contributed to or amplified the scarring aspects, but alone did not cause 
the full blown syndrome. 

6. Pure L-tryptophan alone, at doses comparable to intermediate doses taken by patients with 
L-tryptophan EMS, caused marked scarring of the pancreas in rats. 

(2) Clinical studies: 

Our clinical studies (N. Engl. J. Med. 322:874-881, 1990; Arth. Rheum. 35:1097-1105, 
1992) indicated that while abnormalities of the tryptophan metabolic pathway (the body's chemical 
breakdown pathway) are found in patients with this syndrome, these are caused by exposure to 
inflammation or chemicals important in inflammation, called inflammatory mediators. Thus, the 
changes in the body's way of breaking down tryptophan are not something that the patients were 
born with, rather they result from inflammation. The contribution of variable individual 
susceptibility in relation to other metabolic pathways has not yet been fully elucidated. 

(3) Animal studies: 

Our most recent animal study, (Journal of Clin. Invest. 91:804-811, 1993) cor f: rms and 
extends our initial animal study in rats (Journal of Clin. Invest. 86:1757-1763, 1990), and shows 
that 

1. Treatment with case-associated (impure) L-tryptophan was associated with development of 
one of the main pathologic characteristics of the syndrome, a more than two- fold increase in 
thickness (scarring) of the tissue surrounding muscle (the fascia). 

2. Treatment with case-associated L-tryptophan was also associated with increased activity of 
the white blood cells important in immunity and inflammation. 

3. Treatment with the synthetic contaminant 1,1 Lethylidenebis [L-tryptophan], (EBT), alone 
was associated with an approximately two-fold increase in fascial thickening (scarring). 

4. Treatment with non-case-associated L-tryptophan (pure L-tryptophan) alone was 
associated with a mild but significant increase in fascial thickness (scarring). 

5. All groups of animals receiving case-associated L-tryptophan, non-case-associated L- 
tryptophan, EBT alone, or EBT plus non-case-associated L-tryptophan, developed significant 
and marked scarring of the pancreas. 

6. Only animals receiving case-associated L-tryptophan showed both a more than two-fold 
increase in fascial thickness and increased activity of the white blood cells important in 
immunity and inflammation. 

Other animal studies (R. Silver et al. Arth. Rheum. 1993; M. Jones et al. Arth. Rheum. 1992; 
A. Weller et al. J. Immunol. 150:172A;1993) have confirmed that impure L-tryptophan or one of 
the synthetic impurities alone (EBT) are associated with many of the features of the syndrome, and 
that pure L-tryptophan itself is also associated with some although milder features of the 
syndrome, as well as evidence of scarring in other tissues. 



233 



Implications for safety of food additives, herbals and amino acids: 

In addition to the specific relevance of these findings for L-tryptophan itself, these studies have 
important implications in several areas relating to the safety of dietary supplements in general. 

(1) Categories of risks of undefined products that people ingest: 

There are a large variety of types of risks, related to the large variety of types of products that 
can be ingested, as well as the variety of methods of production of these products. Simply put, 
there are: 

1. products that are generally recognized as safe; 

2. products that are safe at certain doses and in certain contexts (i.e. treatment of specific 
diseases), but unsafe at other doses and under certain conditions; 

3. products that are unsafe at any dose. 

These risks can be categorized in more detail as follows: 

1. risks related to production and purification methods 

2. known physiologic and pharmacologic, i.e. dose-related effects of the active components of 
such products 

3. previously undefined side effects or toxic effects of such products 

4. innocent exposure to undeclared illegal compounds which have been added to products 

5. exposure to known toxins 

6. exposure to known naturally occurring biologically active components of the product with 
well defined serious medical side effects when ingested in uncontrolled doses, in combination 
with certain drugs, or in the context of underlying medical illness. 

7.These problems are greatly amplified when children ingest these products. 

(2) Categories of risks represented by L-tryptophan: 

In this context, L-tryptophan associated with EMS represents a product which falls under three 
categories of risks, and in fact represents a worst-case scenario of the multiple potential risks that 
can be associated with such products. These risk categories are: 

1. production standards-related risks (impure preparation) 

2. known pharmacological dose-related effects (L-tryptophan in tablet form, but not as a 
component of foods is associated with increased brain serotonin, the brain chemical important 
for sleep and mood.) 

3. a potential toxic, and previously unrecognized risk (scarring of the pancreas) 

The argument is frequently made that since a key element in the cause of the EMS epidemic 
was impure L-tryptophan, EMS is not a good example of the risks of unregulated food 
supplements. Even if this were the case, it is clear that tryptophan itself has risks, such as scarring 
of the pancreas in rats, which need to be better defined in humans. However, contamination or 
impurity of a product, as a result of lower production standards, is clearly a category of risk 
associated with unregulated food supplements. Evidence for this is provided by the fact that the 
EMS epidemic did not occur in Canada, where L-tryptophan was sold as a drug, as it was in most 
countries world-wide. All of the few (under 10 cases) which occurred in Canada occurred in 
relation to exposure to L-tryptophan purchased in the United States. Even if screening procedures 
for drugs are imperfect, the magnitude of such epidemics can be contained, and appropriately dealt 
with, as occurred in Germany, where L-tryptophan was sold as a drug. Approximately 100 cases 
occurred in Germany, before the problem was corrected, as compared to the thousands that went 
undetected in the United States. 

That the impurities alone are not a sufficient explanation for the syndrome, but that L- 
tryptophan itself contributes to it and therefore itself carries some risk, is supported not only by 
the animal studies described above, but also by the long-standing, albeit low levels of occurrence 
of the syndrome prior to the 1989 epidemic, (up to 7% of EMS cases), and its occurrence in 
association with compounds related to L-tryptophan (L-5-hydroxytryptophan). Although at this 
time we have no definitive explanation to account for these earlier cases, several possibilities exist 
including the possibility that there is a small segment of the population which is more sensitive to 
the scarring effects of L-tryptophan alone, in the absence of contamination. On the other hand, 
sporadic contamination may have occurred, thereby affecting only a few persons intermittently. 
Lastly, some cases reported as EMS may represent a background level of similar diseases of 
unknown cause, which are now being reported due to the high level of publicity that EMS has 
received. This last possibility occurs frequently in medicine, because the body has limited ways of 
reacting to insult, and certain tissues respond in the same way to damage by a variety of different 
environmental exposures. 



234 



(3) Predicting risks: 

There is virtually no material to which we are exposed that is completely risk-free. The decision 
to expose an individual to the potential risks of a material in medical and scientific terms, 
particularly if that material is being used to modify a medical condition, can be made by weighing 
the potential risks of the product against its potential benefits. In order to make such a judgment, 
one must have knowledge of the chemical nature of the material, the amount of material to which 
one will be exposed, and the situations under which such exposures are safe, beneficial or 
harmful. In order to adequately define such situations, rigorous standards of scientific proof must 
be applied. While man may draw arbitrary distinctions between different categories of products 
against which different standards of proof of safety should be applied, nature does not draw such 
distinctions. A toxic product is toxic whether or not we are capable of recognizing that toxicity. 
Redefining a material in semantic terms does not remove from it the risk that it carries. Only by 
adequately defining that material in chemical, biological and toxicological terms can we minimize 
its risk to the individual. Rigorous methods and standards of scientific proof have been developed 
because our ability to identify such risks by any single method is imperfect. 

Proof of causation in scientific terms: 

The argument is frequently made that many food supplements are highly effective in treating 
a variety of conditions or conferring protection from disease. In notable instances, such as Vitamin 
E's protective effects on the heart, the conclusions were based on rigorous scientific methodology 
in well controlled clinical studies conducted in large numbers of patients. However, frequently 
claims for beneficial effects are based on testimonial reports by patients who have taken such 
products. Testimonial reports, termed anecdotal evidence, are not sufficient proof of cause and 
effect of either the benefits or the harmful effects of a product. Such reports can provide important 
initial clues but alone do not prove that an effect is caused by a product. Such associations can 
occur by chance alone or as a result of the perceived benefit of the product, termed the placebo 
effect. Rigorous scientific methodology significantly reduces the possibility that an observed 
association is the result of chance alone or the placebo effect. In addition, validation often requires 
confirmation by several different methods, to minimize the possibility that a faulty or insensitive 
method led to a false conclusion. No one method of proof is perfect. Therefore a variety of 
approaches must be applied, and the results of such studies, if all pointing in the same direction, 
constitute stronger evidence for a causal link between an exposure and an effect. 

Thus, standards of proof exist on a continuum, from anecdotal testimony to many well 
controlled studies using a variety of methodologies. Since the aim of the exercise is to predict to the 
best of our ability a product's risks and prevent them, the closer one approaches full testing on the 
continuum, the closer one will be to achieving the desired goals of predicting efficacy and 
providing safety. Where to draw the line on this continuum of standards of proof is a difficult 
ethical dilemma, particularly if one includes in the equation the cost and time involved in such 
testing. However, one cannot ignore in the equation the cost in terms of human life if inadequate 
product testing results in toxicity and death. 

The L-tryptophan EMS epidemic can be viewed as a case study in the multidisciplinary 
analysis of disease causation after an environmental exposure. It also represents an example that 
such associations can go unnoticed, sometimes for many years, if the causal link is not made and 
then actively sought. Therefore, although history of safe use can be a valuable first step in 
establishing benefit of certain materials, it is does not necessarily constitute sufficient proof of 
safety. 

Possible reasons for increased demands for food supplements: 

One reason that these issues are difficult to manage, is that they tap into a need which clearly 
exists. The size of the dietary supplements market, and the tenacity with which consumers continue 
to demand easy access to these products, are indicative of the significance of this need. These 
issues strike deeply at emotions which go to the core of the American national psyche, but at the 
same time tap into some of our deepest human fears. At one extreme is our commitment to freedom 
of choice: the profound determination that no one should interfere with our inalienable right to 
choose the food we eat or the remedies for our bodies. At the other extreme is the fear that is 
engendered by the increasingly complex ways in which our food is processed, and the increased 
distance between consumer and producer, resulting in the products that we ingest being somewhat 
unknown and mysterious, and therefore frightening. People as a result have a desperate desire to 
return to more natural products, whether for use as foods or drugs. Such needs may be amplified 



235 



in an increasingly technologically based society, in which health care is so technologically 
sophisticated that most individuals have a sense that the care of their own bodies is out of the realm 
of their control. Use of food supplements is one way that people feel that they can exercise control 
over their own health. It is tempting therefore to assume, as did the L-tryptophan patients, that 
'natural' is safe, and that use of 'natural' products for treatment of medical conditions affords the 
individual greater control over their own health than would yielding their bodies to the 
uncontrollable technologically-based world of medical science. 

However, the risks outlined above associated with the large array of 'natural' products 
available to the consumer, the fact that many products sold as 'natural' are in fact highly processed, 
and most vividly, the occurrence of the L-tryptophan EMS epidemic, indicate the false sense of 
security that can be provided by the assumption that 'natural' is safe. Only knowledge can 
guarantee safety, true control over our environment, and freedom of choice. Uninformed choice is 
not freedom, particularly if that choice carries with it a risk of death. 



^^ 



Esther M. Sternberg, M.D., Chief, 

Unit on Neuroendocrine Immunology and Behavior, 

Clinical Neuroendocrinology Branch, 

National Institute of Mental Health, National Institutes of Health, 

Bethesda, MD 20892 



236 



Mr. chairman: 

Thank you for the opportunity to appear before the subcommittee today. I am Dr. Esther 
Sternberg, Chief of the Unit on Neuroendocrine Immunology and Behavior at the 
National Institute of Mental Health. 

Two years ago, the last time I testified before this subcommittee, the hearings were 
directed at the FDA's regulation of the dietary supplement L-tryptophan. Two years had 
then elapsed since the outbreak of the L-tryptophan EMS epidemic. 

The late Congressman Ted Weiss' opening statement read: "Millions of Americans have 
used the dietary supplement L-tryptophan to treat a variety of medical conditions 
inrlnrl i nf irrnmnin i l l 1 1 ajgB nnri p i mm laMB B^ri—t These consumers were led to 
believe that L-tryptophan was safe, and they were misled. ...this is a tragedy that should 
never have happened." 

Across the United States in the summer and fall of 1989. m nmiiim;d 1500 to 5000 
people who had ingested the amino acid L-tryptophan became ill with a deadly, crippling 
disease. 

Since I last testified, at least 6 more deaths have been -ArfwitfPefy attributed to -fc- 
TTy4MHglMui EMS, with a total of 37 deaths. ~*"~ ' 

As a result of widespread scarring throughout their bodies, 60% of the surviving patients 
are left in chronic pain, crippled, unable to breath, or face life-threatening heart 
arrhythmias . 

At the 1991 hearing, eo ngreoaniaii Ciaig^T-li umas o f- W yoming asked "What do we do 
now to a 1 * ciid this from happening again?" 

It is striking to me that I am now once again before this committee, but i 
question, rather to answer the opposite question: should we JwthoT 
/YA*£ ^;> supplements, of which L-tryptophan was classed as a member, in order to provide the 
public with greater freedom of choice? v r»..-r* ... -.^.i J,t* 

You have asked me to update the committee on the results of our research into the causes 
of L-tryptophan EMS in order to determine the safety of such a move. 

Two things have now become apparent. Not only is the impure L-tryptophan capable of 
causing the full-blown syndrome, but pure L-tryptophan contributes to it and alone causes 
severe scarring in other organs. 

It also has long been known that L-tryptophan in tablet form, but not as a component of 
foods, has dose-related effects on brain chemicals. 

In this context, L-tryptophan associated with EMS represents a product which falls under 
three categories of risks, that isi 

1. production standaidsJ-elated risks associated with impurities 

2. toxic effects suchlas scarring of the pancreas 

3. dose-related risksl related to the natural effects of the chemical 

L-tryptophan illustrates the fact that an individual product can pose multiple risks. 



237 



There is virtually no product to which we are exposed that is completely risk-free. In 
order to judge whether it is worth taking a risk, one must weigh potential risks against 
potential benefits. 

In order to do so, one must have detailed knowledge of the chemical nature of the 
material. 

This knowledge is derived from a range of standards of testing which lie on a continuum 1 , 
from testimonial reports to well controlled studies using many methodologies. 
Testimonial reports are not sufficient proof of either a product's benefits or of its harmful 
effects. 

Since our goal should be to predict to the best of our ability a product's risks and prevent 
them, the closer one approaches full testing on the continuum, the closer one will be to 
achieving the desired goals of predicting efficacy and providing safety. 

Where to draw the line on this continuum and whether to market a product before or after 
it has been fully tested, is a difficult ethical dilemma. One must balance the cost and time 
involved in such testing against the cost in terms of human life if inadequate product 
testing results in toxicity and death. 

The L-tryptophan EMS epidemic can be viewed as a case study in the multidiscrplinary 
analysis of cause of disease after an environmental exposure has occurred. It is also an 
example that such associations can go unnoticed, sometimes for many years, if the causal 
link is not made and actively sought. Therefore, although history of safe use can be a 
valuable first step in establishing the benefit of a product, it is not sufficient proof of 
safety. 

In our increasingly technologically based society people feel that the care of their own 
bodies is out of the realm of their control. Use of food supplements is one way that 
people feel that they can exercise control over their own health. 

It is tempting therefore to assume, as did the L-tryptophan patients, that 'natural' is safe, 
and that use of 'natural' products for treatment of medical conditions gives people greater 
control over their own health than would yielding their bodies to the uncontrollable 
technologies of medical science. 

In fact, absence of knowledge of the chemical nature of the product, its risks, and the 
quantities to which one is being exposed, actually gives consumers less control over their 
own health than if they were ingesting a well defined product. 

Only knowledge can guarantee safety, true control over our environment, and freedom of 
choice. 

The occurrence of the L-tryptophan EMS epidemic most vividly illustrates the false sense 
of security that can be provided by the assumption that 'natural' is safe. 

I hope that the next time I testify before this committee it will not be to once again 
address the cause of a future epidemic. I hope that you will not again be asking how to 
prevent such tragedies from happening. 

Because uninformed choice is not freedom, particularly if that choice carries with it a risk 
of death. 



238 

Mr. Towns. Dr. Huxtable. 

STATEMENT OF RYAN J. HUXTABLE, Ph.D., UNIVERSITY OF 

ARIZONA 

Dr. Huxtable. Mr. Chairman, herbal preparations are activity 
promoted and widely used in the United States. Two aspects of con- 
cern to me are safety and efficacy. Due to the short time, I can dis- 
cuss only the first one. 

Many plants are intrinsically dangerous because they rely on 
toxic chemicals to protect themselves from predation and other 
threats. 

Humans recognize how dangerous plants can be in that of the 
hundreds of thousands of species in the world, we rely on only a 
few dozen for food. They have been selectively bred to reduce tox- 
icity. 

Despite this, we still need to boil beans vigorously to inactivate 
the hemagglutinins they contain; we still need to store potatoes in 
brown bags. Many believe that if something is natural, it is safe. 
However, claws evolved in the tiger not for our benefit but the ti- 
ger's. By the same measure, chemicals evolved in the plants to pro- 
tect the plant, not the consumer of the plant. 

An appeal is often made to traditional practice to justify the safe- 
ty of herbs. Traditional practice, however, cannot be relied on to de- 
tect chronic toxicity where illnesses such as cancer or liver disease 
may develop over a long period and where the association with 
herbal use may not be recognized. 

For example, comfrey has been used as a herb for 2,000 years. 
Books have been written extolling its merit. But now we know that 
comfrey can cause serious liver disease and cancers. 

An increasing number of poisoning cases has been documented, 
and it is clear that people have been poisoned for centuries; but the 
association between the cause and consequence had escaped detec- 
tion. Although comfrey is banned in several countries, there is no 
ban in this country. The herb industry claims that it has volun- 
tarily withdrawn comfrey, but I have with me samples purchased 
within the last 2 weeks. 

Traditional use of herbs involved occasional consumption for the 
treatment of specific symptoms. Now, however, enriched extracts 
are being sold for daily use. Comfrey preparations carry the rec- 
ommendation that two to three capsules be taken with each meal. 
Such consumption presents far greater risks. 

If herbs present such risk, why are the documented cases of poi- 
soning relatively few? Let me draw a comparison with tobacco. To- 
bacco has been used for 400 years, but it has only been in the last 
30 years that an association with cancer has been suspected. It has 
taken many years of expensive research by many people to estab- 
lish the connection. 

In a similar manner, herbal poisonings are difficult to inves- 
tigate, and few people are investigating them. They typically in- 
volve nonspecific conditions such as hepatitis or cirrhosis develop- 
ing over a period of time. 

It is often difficult to get accurate information as to what the pa- 
tient consumed and how much was consumed. There is no mecha- 
nism for recording cases of poisoning. 



239 

A further major problem with pharmacologically active plants is 
lack of standardization. If you take an adult aspirin tablet, you can 
be assured that you are getting precisely 325 milligrams, no more 
and no less. With plants, however, the concentrations of active in- 
gredients varies enormously. 

With comfrey capsules, we have found an 11-fold variation from 
brand to brand in the concentration of toxic alkaloids. Consuming 
a "high" brand carries far more risk than consuming a "low" brand, 
yet the consumer has no way of knowing the level of toxins. 

Botanical identification, alone, therefore, is insufficient for deter- 
mining the risks — pharmacological or toxicological effects of an 
herb. 

Investigation of herbal poisonings is rendered more difficult by 
the problem of identifying the plants involved. Commercial herbal 
preparations are often poorly labeled complex mixtures. Even 
where botanical names are given, they are sometimes wrong. 

Herbs can also be adulterated. Imported herbs have been found 
to contain synthetic steroids and other manufactured drugs. It is 
argued that pure chemicals might be isolated from them. No phar- 
macologist can accept this. In the pseudoscience of the Middle 
Ages, many ingredients were mixed together and the rarer the in- 
gredients were the more efficacious the mixture was supposed to 
be. 

Herbalists tell us that herbs contain other compounds which 
modify and ameliorate undesirable actions of the pure principles. 
That is to say, the mixture of compounds in a crude plant extract 
has properties that cannot be seen with the pure components. 
Again, no pharmacologist can accept this. It is true that the action 
of a compound can be modified by other compounds. 

Imperfect as it is, the classic pharmacological approach has given 
us quinine instead of the bark of a South American tree, penicillin 
instead of a fungus, vinscristine and vinblastine in place of an Afri- 
can flower, aspirin in place of willow bark, colchicine in place of a 
crocus bulb, reserpine instead of an Indian root, and ephedrine in 
place of a Chinese gymnosperm. 

Who, with any knowledge, can doubt that these isolated drugs 
are more efficacious than the use of the whole plant could be? 

It would be irrational to allow a reversion to the polypharmacy 
of the Middle Ages, with its undemonstrated beliefs in the intrinsic 
merits of complex natural mixtures. 

I acknowledge that traditional medicine is a priceless resource 
for the uncovering of pharmacological useful substances. But the 
active ingredient should be isolated, examined, tested, and used 
within the great intellectual tradition established by pharmacology. 

Thank you, Mr. Chairman. 

Mr. Towns. Thank you. 

[The prepared statement of Dr. Huxtable follows:] 



240 



Written Testimony Submitted to Hearing on FDA 's Regulation of Dietary Supplements 

Tuesday, July 20, 1993 
Human Resources and Intergovernmental Relations Subcommittee of the House Government 

Operations Committee 



Herbal preparations are actively promoted and widely used in the United States. Because 
such preparations are natural, many people consider them to be safe. Two health-related aspects 
of herbs that are of concern to me are safety and efficacy. Due to the short time I have, I will 
stress the first issue. 

Many plants are intrinsically dangerous because they rely on toxic chemicals to protect 
themselves from predation, and from insects, bacteria, viruses and other threats. Humans 
recognize how dangerous plants can be in that of the hundreds of thousands of plant species in 
the world we rely only on a few dozen for the bulk of our calories. These few dozen plants 
have been selectively bred to reduce toxicity. Despite this, we still need to store potatoes in 
brown plastic bags to minimize the light-induced increase in toxins. We still need to boil beans 
vigorously to inactivate the toxic hemagglutinins they contain. Humans recognize the potential 
toxicity of plants in the large number of potent drugs we have that are isolated from plants. 
Quinine, digitalis, morphine, cocaine, caffeine, strychnine, vinblastine, camphor, taxol and LSD 
are all plant chemicals. We recognize the power that plants have in that about 25% of all 
prescriptions in the United States are for natural products, while another 25% are for substances 
derived from modification of a natural product. 

Many believe that if something is natural, it is safe. However, claws evolved in the tiger not 
for our benefit, but for the tiger's. By the same measure, chemicals evolved in plants to protect 
the plant; not the consumer of the plant. The chemical constituents of herbs should, therefore, be 
viewed in terms of assessing toxicity or health risk as one would view any manufactured drag 
or chemical. 

An appeal is often made to traditional practice to justify the safety of herbs. This is 
acceptable in terms of acute toxicity, where if a plant such as deadly nightshade is consumed, 
poisoning occurs within a short period. Traditional practice, however, can not be relied on as a 
criterion of lack of chronic toxicity, where illnesses such as cancer or liver disease may develop 
over a long period, and where the association with herbal use may not be recognized. For 
example, comfrey has been used as a herb for 2000 years. Books have been written extolling its 
merits for many conditions. But now we know that comfrey can cause serious liver disease and 
cancers. An increasing number of human poisoning cases have been documented, and it is clear 
that people must have been poisoned by comfrey for centuries, but the association between 
cause and consequence had escaped detection. 

Although comfrey is banned in several other countries, there is no ban in this country. The 
industry claims it has voluntarily withdrawn comfrey, but I have here some samples purchased 
two weeks ago. 

Traditional use of herbs involved occasional consumption for the treatment of specific 
symptoms. Now, however, enriched extracts are often sold with the recommendation tliat they 
be taken on a regular basis. Comfrey preparations - containing toxic and carcinogenic alkaloids - 
are typically sold with the recommendation that 2-4 capsules be taken with each meal. 
Consuming large amounts of such enriched preparations on a daily basis presents far greater 
risks than the drinking of an occasional cup of comfrey tea, or the use in cookery of small 
amounts of potentially toxic plants such as rosemary, nutmeg or anise. 

If herbs present such risks, why are the documented cases of poisoning relatively few? Let 
me draw a comparison with tobacco. Tobacco has been heavily used in western countries for 

1 



241 



four centuries. Yet it has only been within the last 30 years that an association with lung and 
heart disease has been suspected. It has taken many years of expensive research by many people 
to establish what now appears to most of us to be an obvious connection. In a similar manner, 
herbal poisonings are difficult to investigate, and few people are investigating them. They 
typically involve nonspecific conditions such as hepatitis or cirrhosis developing over a period 
of time. It is often difficult to get accurate information as to what the patient consumed and how 
much was consumed. There is no mechanism for recording cases of poisoning. One indication 
of the kind of public health problems associated with the use of herbs is given by a Swedish 
study. A group of 53 patients with hepatitis of unknown cause was asked to stop taking all 
herbs for 6 weeks. At the end of this period, liver function tests had normalized in 52 of the 53. 
Probably any hospital in the country could tell you of unexplained deaths that might have 
involved herbs. 

A major problem with pharmacologically active plants is standardization. If you take an adult 
aspirin tablet, you can be assured that you are getting precisely 325 mg; no more and no less. 
With plants, however, the concentrations of active ingredients can vary enormously, depending 
on the part of the plant used, the place it was grown, the year and rime of year it was harvested, 
how it was handled and stored, and many other factors. When digitalis used to be prescribed as 
a leave rather than a pure drug, the leave had to be standardized before being sold. With 
comfrey capsules, we have found an 11 -fold variation from brand to brand in the concentration 
of toxic alkaloids. Consuming a "high" brand carries far more risk than consuming a "low" 
brand, yet the consumer has no way of knowing the level of toxins in one brand as compared to 
another. Botanical identification alone, therefore, is insufficient for determining the 
pharmacological (or toxicological) effect of a herb. 

Investigation of herbal poisonings is rendered more difficult by the problem of identifying 
the plants. Commercial herbal preparations are often complex mixtures of plants, often identified 
on the packet in a mixture of mock Latin and English rather than proper botanical names. Even 
where botanical names are given, they are not infrequently wrong. One study in the late 1970s 
showed that up to 60% of the ginseng preparations sold contained litde or no gingseng. In 
another study, about half of samples labelled as common comfrey were found on examination to 
be prepared from a different, and more toxic, plant. The highly toxic plant, Jimson weed, has 
been sold by mistake for comfrey. Echinacea has become a popular herb, yet a less expensive 
plant, Parthenium, has been sold as Echinacea. Imported herbs have been found to contain 
synthetic steroids and other manufactured drugs such as diazepam (better known by its 
tradename, Valium). These problems could be controlled if there were a requirement for proper 
labelling with proper botanical names listed in order of abundance, and a requirement that 
voucher specimens of the plants used be deposited at some registry. 

Claims unsubstantiated by scientific investigation are often made for herbs. Claims may be 
backed up by personal testimonials which, although psychologically persuasive, carry little 
scientific value. At one recent meeting, for example, an industry representative talked of the 
value of herbs, using the case of her infertile brother-in-law who fathered a child after taking a 
preparation containing prostate extract. However, an endocrinologist in the audience pointed out 
that prostate contains potent steroids that suppress fertility, and that such a preparation could not 
possibly be responsible for the happy ending to the story. When herbs are sold for losing 
weight, increasing sexual performance, retarding aging, or producing rejuvenation, the claims are 
intrinsically to be suspected. Attached without further comment are information sheets for 
various products that contain misleading claims. 

One of the driving forces for the use of herbal preparations is the argument that crude plant 
extracts have advantages over the use of the pure chemicals that might be isolated from them. 
No pharmacologist can accept this. Pharmacology replaced the pseudo-science of the pre- 



242 



modern period, when many ingredients were mixed together, and the rarer the ingredients were 
the more efficaceous the mixture was supposed to be. This gave us the witches' brew in 
Macbeth, with its 'eye of toad and wing of bat*. Pharmacology replaced this by isolating pure 
compounds, and quantifying their actions. Herbalists tell us that herbs contain other compounds 
which modify and ameliorate undesirable actions of the pure principles. That is to say, the 
mixture of compounds in a crude plant extract has properties that can not be seen with the pure 
components. Again, no pharmacologist can accept this. It is true that the action of a compound 
can be modified by other compounds. There can be alterations in absorption, binding, 
distribution, metabolism, and actions at site. All of these effects, however, are susceptible of 
rational analysis. There is no reason a priori to suppose that secondary metabolites co-occurring 
in the plant are going to have beneficial effects on the therapeutic actions of an active 
ingredient. What selective evolutionary pressure on the plant could account for such a 
phenomenon? Where such interactions occur, they are happenstance. 

Imperfect as it is - imperfect as any human endeavor must be - the classic pharmacological 
approach has given us quinine instead of the bark of a South American tree, penicillin instead of 
a fungus, vincristine and vinblastine in place of an African flower, aspirin in place of willow 
bark, colchicine in place of a crocus bulb, reserpine instead of an Indian root, and ephedrine in 
place of a Chinese gymnosperm. Who, with any knowledge, can doubt that these isolated drugs 
are more efficacious than the use of the whole plant could be? Furthermore, the study of pure 
agents has allowed their effective use in areas far removed from their use in traditional 
medicine. The antimalarial cinchona bark yielded quinine, now more important in the treatment 
of heart arrhythmias. The tranquilizing Rauwolfia plant yielded reserpine, now used as an 
antihypertensive. The pain-killing willow bark resulted in aspirin, used prophylactically as an 
antithrombotic agent Vincristine and vinblastine from the Madagascar periwinkle, used 
traditionally as a panacea, are now mainstays in the treatment of leukemia. 

The enormous advances in public health in this country within the past century has been 
powered by rational pharmacology. It would be irrational to allow a reversion to the 
polypharmacy of the middle ages, with its undemonstrated beliefs in the intrinsic merits of 
complex natural mixtures. At the beginning of this century, life expectancy in the United States 
was a little over 40 years. Life expectancy is still little better than this in much of the world 
reliant solely on traditional medicines. 

I acknowledge that traditional medicine is a priceless resource for the uncovering of 
pharmacologically useful substances. I have frequently written on this subject But the active 
ingredients in traditional herbs should be isolated, examined, tested and used within the great 
intellectual tradition established by pharmacology. 

The following articles also contain information relevant to the issue of herbal safety (1-15). 
Of these articles, the ones in boldface are submitted as part of this written testimony 
(2-9,11-13). 

Respectfully submitted. 



Ryan J. Huxtable PhD 
Department of Pharmacology 
University of Arizona College of Medicine 
Tucson, Arizona 85724 



243 



1. FOX, D. W., M. C. HART, P. S. BERGESON, P. B. JARRETT, A. E. STILLMAN and R. 
J. HUXTABLE. Pyrrolizidine (Senecio) intoxication mimicking Reye's syndrome. Journal of 
Pediatrics 93: 980-982, 1978. 

2. HUXTABLE, R. J. Herbal teas and toxins: novel aspects of pyrrolizidine poisoning in 
the United States. PerspecL Biol. Med. 24: 1-14, 1980. 

3. HUXTABLE, R. J. Human health implications of pyrrolizidine alkaloids and herbs 
containing them. In: Toxicants of Plant Origin, Vol I: Alkaloids, edited by P. R. Cheeke. 
Boca Raton, Florida: CRC Press, 1989, p. 41-86. 

4. HUXTABLE, R. J. Human embryotoxicity of pyrrolizidine-containing drugs. 
Hepatology 9: 510-511, 1989. 

5. HUXTABLE, R. J. The harmful potential of herbal and other plant products. Drug 
Safety 5 (Suppl. 1): 126-136, 1990. 

6. HUXTABLE, R. J. The toxicology of alkaloids in foods and herbs. In: Handbook of 
Natural Toxins: Vol. 7 Food Poisoning, edited by A. T. Tu. New York: Marcel Dekker, 
1992, p. 237-262. 

7. HUXTABLE, R. J. Comments on the risks of pyrrolizidine poisoning from comfrey 
(Symphytum). 1992, (UnPub) 

8. HUXTABLE, R. J. Neurotoxins in herbs and plant foods. In: The Vulnerable Brain and 
Environmental Risks, Vol I: Malnutrition and Hazard Assessment, edited by R. L. 
Isaacson and K. F. Jensen. New York: Plenum Publishing, 1992, p. 77-108. 

9. HUXTABLE, R. J. The myth of beneficent nature: The risks of herbal preparations. 
Ann. Internal Med. 117: 165-166, 1992. 

10. HUXTABLE, R. J. American health quackery. Trends Pharmacol. Sci. 1993.(In Press) 

11. HUXTABLE, R. J. and D. V. C. AWANG. Pyrrolizidine poisoning. Amer. J. Med. 89: 
547-548, 1990. 

12. HUXTABLE, R. J., J. LUTHY and V. ZWEIFEL. Comfrey pepsin preparations - a 
warning. New EngL J. Med. 315: 1095, 1986. 

13. RIDKER, P. M., S. OHKUMA, W. V. MCDERMOTT, C. TREY and R. J. 
HUXTABLE. Hepatic veno-occlusive disease associated with the consumption of 
pyrrolizidine-containing dietary supplements. Gastroenterology 88: 1050-1054, 1985. 

14. STILLMAN, A. E., R. HUXTABLE, P. CONSROE, P. KOHNEN and S. SMITH. Hepatic 
veno-occlusive disease due to pyrrolizidine poisoning in Arizona. Gastroenterology 73: 
349-352, 1977. 

15. STILLMAN, A. E., R. J. HUXTABLE, D. W. FOX, M. C. HART and P. S. BERGESON. 
Pyrrolizicline (senecio) poisoning in Arizona: severe liver damage due to herbal teas. Arizona 
Med. 34: 545-546, 1977. 



244 



PERSPECTIVES IN BIOLOGY AND MEDICINE 

Volume 24 Number I ■ Autumn 1980 



HERBAL TEAS AND TOXINS: NOVEL ASPECTS OF 
PYRROLIZID/NE POISONING IN 
THE UNITED STATES 

RYAN J. HUXTAULE* 



This article reviews the discovery of pyrrolizidine alkaloid poisoning 
in the United States caused by the drinking of herbal tea and describes 
some of the difficulties involved in establishing a causal relationship 
between exposure to these alkaloids and the delayed appearance of roxic 
symptoms. In addition, some of the more general problems presented by 
the widespread use of herbs in various forms are addressed. First, how- 
ever, a brief overview is given of the toxicity of this class of alkaloids. 

Occurrence and Toxicity of Pyrrolizidine Alkaloids 

Pyrrolidines occur in many plant families, including Boraginaceae, 
Compusitae, Gramineae, Leguminosae, Orchidaceae, Rhizophoraceae, 
Santalaceae, and Saptoaceae. Part structures of these alkaloids are illus- 
trated in figure 1. Toxic alkaloids contain an unsaturated ring. These 
alkaloids, and the plants in which they occur, are hepatotoxins, produc- 
ing veno-occlusive disease, hepatomegaly and — with some alkaloids — 
liver cancers [1]. 

There is good evidence that the mechanism of toxicity involves a "le- 
thal synthesis" in the liver whereby the alkaloids are metabolized to 
pyrroles (fig. 1). Pyrroles are chemically active and serve as biological 
alkylating agents by ihe mechanism shown in figure 2, in which groups X 

The author thanks Charles Mason, Curator, University of Arizona Herbarium, lor plant 
identifications. Laboratory work, supported by USPHS grant HI.-20087. 

* Department ui Pharmacology, Health Sciences Center, University ot Arizona, Tucson, 
Arizona 85724. 

H 19H0 by The University oi Chicago. 003 1-5982/8 1/240 1 -0208$0 1.00 

Prnftrdwes m Biulugy ami Medicine • Autumn 1980 1 



245 



and Y represent nucleophilic portions of proteins or nucleic acids, such 
as sulfhydryl groups [2]. Alkylation is a widespread mechanism ol toxic- 
ity and takes place with many mutagens and carcinogens apart from 
pyrrolidines. 

Human Exposure to Pyrrolizidine Alkaloids 

Pyrrolizidine alkaloid poisoning is a public health problem in many 
areas of the world. This is partly due to the wide botanical and geo- 





MfPATOTOXIC WON-Ht P»TOT OXIC 





n-oxtsc p t * * o u t 



P y *ii ouzioinc Paut Stductukcs 



Fie. I. — Pyrrolizidine pan structure. The omitted portion of the structure is usually a 
cyclic diester grouping (- CO.R.CO -). Toxic aikaloids are metabolized to N-oxides and 
pyrroles. The cyclic diester may also be metabolically hydrolyzed. 



PYRROLE TOXICITY 




R.-C-Cfl CH,0-C-R, 



x\ CH-OC-R, 


X CH, 


X CH,Y 



II ' 



X CH^-C-Rg 



Ftc. 2.— Pvrrole toxicity. Pyrroles formed in the liver are postulated to '*; toxic l?ecause 
of their ability to alkylate nucleophilic groups, such as sulfhydryl (X,Y), on cell mac- 
romolecules. Based on a proposal of Mattocks [2]. 



2 J Ryan J. HuxlabU ■ Herbal Teas and Toxins 



246 



graphical distribution of pyrrolizidine-containing plants. There are two 
major sources of human exposure: accidental contamination of 
foodstuffs and the deliberate use of pyrrolizidine-containing plants in 
herbal preparations. Accidental contamination falls into two categories: 
that of continuous low-level contamination that may last for many years 
and epidemic poisoning caused by occasional massive contamination of 
foodstuffs. Recent examples of the latter occurred both in Afghanistan 
and in India in 1976. These epidemics were caused by Heliolropium and 
Crotaluna species contaminating fields of wheat and being harvested 
along with the grain to make bread. Wheat from the affected area was 
found to contain about 300 mg of Heliolropium seeds per kilogram of 
wheat. The Afghanistan outbreak involved approximately 1 ,600 cases of 
veno-occlusive disease of the liver [3]. Many of these patients died. The 
true scope of the epidemic may have been much larger however, due to 
the fact that the outbreak occurred in a primitive area where health care 
is uncertain and hard to obtain. Furthermore, many exposed persons 
may have suffered long-term deleterious consequences that did not re- 
sult in an immediate clinical picture. The Indian epidemic involved 
fewer people. However, of the 67 recorded cases, 28 died [4]. 

Chronic contamination of foodstuffs has been a problem in South 
Africa. Here the major offending species appear to be Senecio and 
Crolaiana, and the usual route of exposure is that of these plants con- 
taminating grains used to prepare foot! [5]. Senecio poisoning by this 
route has been thought to be responsible for the high incidence of pri- 
mary liver carcinoma in black Africans. This type of exposure no longer 
occurs in the advanced industrialized nations due to the widespread use 
of chemicals for controlling unwanted plants in grain fields. Twenty-five 
years ago, it was not an uncommon sight in the English countryside to 
see fields of grain speckled with bright red poppies and blue cornflow- 
ers. However, this bucolic picture can be seen no more. 

The intentional consumption of plants that contain pyrrolizidine 
alkaloids is a major public health and cultural problem in many areas of 
Africa, South and Central America, and, in particular, Jamaica. There is 
no intent, of course, to poison oneself and others, and the behavior is 
based on folklore and lack of knowledge. Pyrrolizidine-containing plants 
are used to prepare medications, teas, and other ingestible preparations. 
In Jamaica, tor example, an indefinable "bush tea" is prepared by a 
person going into the scrubland that dominates the flora of much of the 
island and collecting leaves, which are subsequently infused, from a wide 
variety of plains. Crolaiana species are the major source of pyrrolizidines 
in bush tea. Pediatric veno-occlusive disease has been of almost epidemic 
proportions in Jamaica, and the medical description of this entity origi- 
nated there [6|. The toxic sequelae of this habit are exacerbated by poor 
nutritional status and by the simultaneous consumption of other toxic 

Ptmprcuve* in Biology and Medicine • Autumn 1980 | 3 



247 



plants. Another major source of poisoning in Jamaica results from the 
consumption of the unripe fruit of the ackee plant (Blig/ua sapida). The 
name derives from a confusion with the breadfruit plant (Artomrpns 
altilis) that Captain Bligh of the Bounty was carrying to Jamaica from its 
original habitat in the South Seas at the time his crew mutinied. The 
unripe ackee fruit contains an agent, hypoglycin. which blocks 
gluconeogenesis in the liver. The resulting illness is known as Jamaican 
vomiting sickness [7]. This points to a general problem in herbal 
poisoning in that the victim has rarely been exposed to one toxic chemi- 
cal. Often, he has been exposed to a variety of plants which modify the 
toxic action of each other, he may be suffering from parasitic diseases 
and poor nutritional status, and the toxicological action of a plain may 
differ quite substantially from that of a purified active principle isolated 
from the plant. One cannot expect pyrrolidine poisoning produced by 
ingestion of a plant to mimic the disease caused by administration of a 
purified alkaloid in a laboratory setting. 

Both Senecio and Crolalana species are used to prepare teas in Africa. 
Extracts of Senecio have even been used in a commercial preparation sold 
to treat conditions as opposed as amenorrhea and menorrhagia [5-J. 

Mexico is another area where there is widespread reliance on herbal 
medications. A highly readable description of the theory and therapy of 
sickness as practiced by Mexicans in a border community has recently 
appeared [8]. 

Until recently, pyrrolizidine poisoning had not been thought to be a 
public health problem in industrialized nations. The occasional case has 
been reported from England, usually involving a recent immigrant to 
the country from areas of the world where use of herbs is more common 
[9, 10]. In such cases, it is often difficult to obtain botanically identifiable 
samples. One case of veno-occlusive disease was ascribed to drinking 
Mate, or Paraguay tea (Ilex species). Such tea is used extensively. In- 
deed, it may be considered to be a national drink of Brazil and the 
neighboring states. There is no evidence that Ilex species contain pyr- 
rolizidine, and it is more likely that the patient in this case had been 
poisoned by pyrrolidines but the plant source was misidentified. The 
only case of pyrrolizidine poisoning reported in the United Stales in- 
volved a recent immigrant from Ecuador who had been exposed to 
herbs presumably containing pyrrolizidine alkaloids before she had en- 
tered this country. After her arrival, she developed veno-occlusive dis- 
ease. However, no sample of the herb was obtained for confirmation ol 
the diagnosis [1 1]. 

Pyrrolizidine Poisoning by Herbal Teas in the United Slates 

The complacent attitude regarding the public health problem of pyr- 
rolizidine alkaloids in the United States has been shaken within the past 



4 [ Ryan J. HiuxlabU • Herbal Teas and Toxins 



248 



2 years. Pyrrolidines are a major cause of livestock poisoning in the 
Northern Pacific States. The offending plant is a European import — 
Senecio jacobea — which has spread over many square miles of pasture 
land. There are increasing indications that pyrrolizidine alkaloids can 
enter the food chain and thus create a potential source of exposure [12, 
13]. In addition, we have documented cases of pyrrolizidine poisoning in 
children in Arizona. Clinical descriptions of two of these cases have been 
provided elsewhere, so only a synopsis will be given here. 

Once case involved a 6-month-old Mexican-American female, admit- 
ted to the hospital with a diagnosis of a typical hepatitis [14]. An astute 
gastioenterologisi, Dr. Alfred Stilhnan, was puzzled by the clinical pre- 
sentation. Questioning of the mother revealed that the child had been 
given a herbal tea, known as gordolobo yerba, over a 2-week period 
prior to admission. The remainder of this herb was obtained, given to 
me, and idenufied as Senecio longilobus. This plant, which is probably 
identical with Senecw douglasii, had been shown by Adams and Govin- 
dachari [15] to contain a mixture of four pyrrolizidine alkaloids in a total 
concentration of about 0.24 percent of dried plant weight. Our analysis 
of the actual sample to which the patient had been exposed revealed an 
alkaloidal content of 0.3 percent, in good agreement with the earlier 
workers. In addition, however, we found 1.0 percent by weight of the 
nonbasic and nonextractable pyrrolizidine N-oxides (lig. 1) [10]. There 
is some dispute as to the toxicity of N-oxides, but they are probably 
equally as toxic as the free alkaloids. The contaminated grain that caused 
the Afghanistan outbreak contained largely N-oxides [3]. Thus this plant 
comained four times the total alkaloids detected by the original workers. 
The alkaloid Iraction was largely riddelliine, and the N-oxide fraction 
was largely reirorsiue N-oxide plus the N-oxides of seneciphylline and 
senecionine [ 17]. 

Based on the mother's recipe for preparing tea, we calculated that an 
amount of tea equivalent to 147 mg total alkaloids had been led to the 
child. We prepared some tea in the laboratory by the mother's recipe 
following a conservative procedure. Water was brought to the boil, re- 
moved from die source of heat, and the correct quantity of herb added 
and stirred in. The tea was allowed to cool to room temperature, filtered, 
and analyzed tor alkaloidal content. Under these conditions 48 percent 
ot the alkaloids present in the sample were extracted. Boiling the tea 
increases the extraction efficiency. On the basis of this demonstration, 
we calculated that the child had received a minimum of 70 mg ot 
alkaloid and a maximum of 147 mg over a 2-week period. Calculations 
of toxicity are complicated by the chronic effect of these substances. 
Some indication ol relative toxicity, however, is given by the LD50 in rats 
over a 72-hour period, following a single intraperitoneal injection: 
senecionine 85 mg/kg, seneciphylline 77 mg/kg, and retrorsine 35 mg/kg 
[1]. The minimum close ingested by the child of 70 mg of a retrorsine- 

Perspeclives in Biology and Medicine ■ Autumn 1 980 | 5 



249 



rich mixture is. therefore, clearly a toxic amount, especially when it is 
considered thai the young of all species are more susceptible to the toxic 
actions of pyrrolidine alkaloids. 1 he child developed cirrhosis, but 
survived. 

The other case involved a 2-month old Mexican-American male ad- 
mitted to the hospital with a diagnosis of Reve's syndrome [16]. The 
patient died 3 days later. Two weeks prior to admission, he had heen 
given gordoloho. This had been sold in popcorn packets as a sore-throat 
remedy by a pharmacy (lis 3). We obtained the material, identified it as 
Senecio longtlohus. and demonstrated the presence ol pyrrolizidine 
alkaloids. This sample was slightly richer in total alkaloids, containing 
1.0 percent N-oxides and 0.5 percent free alkaloids. The sample con- 
tained fewer woody stems than the one fed the first patient, which may 
account for the higher alkaloid content. Coincidentally, based on the 
mother's recipe, we calculated that this patient had consumed almost 
identically the same quantity of alkaloid as had the first patient. The 
most likely quantity ingested was 66 rng, albeit over a shorter period and 
by a lighter infant. 

In one sense, lioth these cases were correctly diagnosed by chance. 
Confirmation of pyrrolidine poisoning was achieved in these cases be- 
cause herbal samples were available for chemical analysis. Usually, in 
cases of poisoning not involving pyrrolidines an association can be 
made between symptomatology and blood levels of the toxin. However, 
with pyrrolidine alkaloids no analytical method has yet been made 
available for the analysis of body fluids or tissue samples. Pyrrolizidine 
alkaloids are largely excreted within 24 hours of exposure, yet 




Fie. 3. — The deadly clown. This packet of herbal tea killed a young child. 



6 Ryan J. Unstable Herbal Teas and Toxins 



250 



symptomatology may not appear for days, weeks, or even months. This 
means the diagnosis of pyrrolidine poisoning must be made on cir- 
cumstantial evidence. In practice, this reduces to (i) liver symptoms in- 
dicative of pyrrolizidine poisoning (especially veno-occlusive disease), (ii) 
analysis for the presence of pyrrolizidine alkaloids in samples of herbs or 
foods the patient has taken, and (iii) pathognomonic changes in liver 
architecture. This is limited to autopsy or biopsy material. 

In the light of the difficulties of diagnosis, we may ask the question as 
to how widespread pyrrolizidine poisoning is in the United States. This 
point is discussed further in the following sections. However, we may say 
that we have come across a number of cases in Arizona of suspected 
pyrrolizidine poisoning. No definite confirmation is possible. Typical 
examples of some of these cases are briefly described. 

A 2-year-old Mexican-American girl was admitted to the hospital with 
jaundice and hepatomegaly. Liver- function tests were markedly abnor- 
mal. An open liver biopsy revealed centrilobular necrosis. For several 
weeks prior to admission, the child had been given gordolobo yerba. 

A 4-month-old Mexican-American girl (weight 4.5 kg) was admitted 
with pneumonia, nephritis, and liver disease initially diagnosed as Reyes 
syndrome. She had been fed a herbal tea on a regular basis for the 
mouth before admission. A sample of tea obtained from the parents 
contained a mixture of plant species, including some composites (the 
family that contains Setucio). However, analysis did not unequivocally 
reveal the presence of pyrrolidines. 

A 62-year-old Mexican- American female died of complications of 
portal hypertension, cirrhosis, hypertension, and hepatic en- 
cephalopathy resulting from the portal hypertension. The patient had 
not consumed alcohol. For the 6 months prior to death she had con- 
sumed several cups a day of tea prepared from gordolobo. 

A 2-month-old Mexican-American boy was admitted to the hospital 
with jaundice and hepatomegaly. He did well in the hospital and was 
released. He was readmitted a short while later with fulminant hepatic 
failure and died. No genetic, infectious, or metabolic cause for the illness 
could be found. A year later, a 2-month-old brother was admitted with 
hepatomegaly. This boy died of hepatic necrosis. The mother had led 
herbal teas to the children, but no samples could be obtained. A pattern 
of improvement in the hospital followed by relapse at home suggests a 
factor — such as herbs — in the home environment as a precipitant of ill 
health. 

Pyrrulizidine-containing Plants in Arizona 

Pyrrolizidine-containing plants known to occur in Arizona are listed in 
table 1. We have added two plants, Bacchans pteronoid.es and Astragulus 

Perspectives m Biology and Medicine Autumn 1980 7 



251 



TABLE 1 
Names of Arizona Spt.cjf.s That Contain Pyrroi.izidinf. Ai.kai.oids 



Scientific Synonyms Common (".tared 



• 



A msinckia intermedia A. echinala Fiddleneck 

A. tesselata ... 

Crotalana pumila ... Rattlebox 

C. sagtUalis ... Rattlebox 

Eupatonum maculalum E bninert Bruner's trumpet 

weed 

Heliotropium curassavtcum ... Quail plant t 

Seneao bigtlovti ... 

S. jacobta Tansy rag-wort 

S. longtlobus S. dougiasn Thread-leafed *t 

groundsel 

S. spartotdes ... Broom groundsel * 

S. vulgaris ••• Common groundsel 

Novel species:^ 

Bacchans pteronoides B. ramalnsa Yerba de pasmo *t 

Astragutus lenttginosus Cystium Milk vctcb. 

leniigtnosum loco weed 



•tt has been documented that stark grate on these species. The other species are probably |rraied also, however. 
tThese species are used mednatty by Indians or other groups. 
(From the author s laboratory. 



Untiginosus, to this list based on the results of the Ehrlich color test in our 
laboratory. Baccharis pteronoides, under the herbal name of yerba de 
pasmo, is widely used as a cold remedy and as a veterinary remedy by 
Mexican-Americans and rural populations throughout the southwest. 
Astragulus lentiginosm is known locally as "loco weed." It has long been 
known to be poisonous to stock, although the toxin had not previously 
been identified. It had been suggested that selenium accumulation, ni- 
trate formation, or an uncharacterized alkaloid "locoine" were re- 
sponsible for the toxin. Our analyses indicate that this plant contains 
toxic pyrrolidine alkaloids, although it may also contain other toxic 
agents. Any of the plants listed in table 2 could pose a health problem as 
a result of consumption by stock, or as a result of direct use by humans. 
Senecio longtlobus is extensively used by at least one Indian tril>e in 
Arizona [18]. Another Seneao plant, S. monoensis, is used by the Seri 
Indians [19]. A tea is made by boiling the roots and is taken as a remedy 
for a cold. This plant has not been reported to contain pyrrolidine 
alkaloids, but it is very likely that it does. 

The use of pyrrolizidine-containing plants is probably widespread in 
many groups, even in the industrialized nations. I have seen such plants, 
for example, in a demonstration herb garden in Quebec. 



8 J Ryan J. Huxtable • Herbal Teas and Toxins 



252 

TABLE 2 

NONEQUIVALENCY OF HERBAL AND LlNNEAN NAMES 
Herbal Linnean 

Gordolobo yerba Senecio longilobus, Gnaphalium 

Macounu, Verbascum thapsus 

Mullein V. thapsus 

Mauzanilla del Rio G. Macounu, G. Wnghlii 

Punthon V . thapsus 

Tobaco cimarrou V. thapsus, Nicotiana tabacum 

Car.delaria V. thapsus 

Vei basco V. thapsus 

Noil — The plains in the nghi-liand column have been documented as being sold under the herbal names in (he 
leli-land column, e.g., at lean ihree plants have been sold as gordolobo; and V thafnui has been sold under ai least six 
herbal names. 



Long-Term Effects of Pyrrolizidine Consumption 

In older children, or adults, disease caused by pyrrolizidines would be 
expected to be cryptic, not resulting in clinical symptoms for months or 
years after exposure. One end result would be liver cirrhosis. The ap- 
pearance of cirrhosis in an adult would probably be attributed to other 
aspects of life-style than herbal-tea drinking. It is of interest to observe 
thai mortality rates from cirrhosis in Arizona are consistently higher 
than the national average. For the years 1970-1975, rates were 14, 12, 
4 1 , 3, 3, and 8 percent over the national rate. It is possible that exposure 
to pyrrolizidine alkaloids is at least one contributory factor to this. 

A further cause for concern is that, in experimental animals, exposure 
to low levels of pyrrolizidine alkaloids results in the appearance of lung 
rather than liver lesions (20, 21]. These lung lesions progress to pulmo- 
nary arterial hypertension and right-ventricular hypertrophy. Again, 
the appearance of lung disease in middle age is unlikely to be attributed 
to prior exposure to herbal teas. Several reports of pyrrolizidine 
poisoning in humans stale that lung disease also occurred [9, 22]. These 
lesions are probably caused by a similar mechanism to the one producing 
liver lesions. The liver releases small quantities of pyrrole metabolites 
into the bloodstream which are then delivered to the next organ in 
line — the lung. Any toxin passing through the circulation of the lung 
comes into intimate contact with the endothelial cells lining the lung 
capillaries. It is likely thai the gross toxic manifestations in the lungs and 
right heart are a consequence of endothelial cell dysfunction, such as 
proliferation and occlusion of capillaries and the production of a throm- 
bogenic cell surface [21]. 



Perspectives m Biology and Medicine ■ Autumn 1980 | 9 



253 



Gordolobo Yerba and Pyrrolizidine Poisoning 

The Arizona cases involved poisoning with teas prepared from Senecio 
longilobus, which had hcen sold under die herbal name of gordolobo 
yerba. Semcio longilobus, commonly known as thread-leaf groundsel, or 
woolly groundsel, grows wild throughout much of the southwesiern 
United States and northern Mexico (fig. 4). In the case of the herb used 
by the first patient, the distribution could be traced. The plant was col- 
lected in Mexico and imported into this country by a major wholesaler. 
This importer is a major supplier of herbs in the western United States 
and even reexports herbs to many communities in northwestern Mexico. 
One may ask why a person would pay a dollar for Vi ounce of a plant 
imported from Mexico that grows freely in southern Arizona. Part of the 
answer is probably ignorance of which plant is which. However, there 
appears to be a deep-rooted belief among poor Mexican-Americans, and 
Mexican-Indian immigrants in this country, that plants from Mexico are 
more efficacious. There is a part religious, part magic belief that the 
closer the plant was collected to the home area of the person the more 
effective it will be. I was told by the importer that Seneao longilobus had 
been imported and sold by his company for 2 generations. 

In the Mexican border town of Nogales, 66 miles from Tucson, we 
purchased a sample of gordolobo yerba which was identified as 
Gnaphalium Macounii. This plant contains no pyrrolizidine alkaloids and 
is similar in appearance to Senecio. Gnaphalium Macounii and other 
Gnaphalium species are commonly used in a number of areas of northern 
Mexico under the cognomen gordolobo. Does this mean that the dis- 




Fig. 4. — Senecio longilobus growing in a typical Southwestern habitat 



10 J R\an J. Huxinble • Hrrhal Ttas nnti Tnxtnx 



254 



tributors oiSenecio made an error and confused Senecw and Gnaphalium? 
I think this is too simple an answer. The identification of a species is 
based on morphological characteristics, whether one is a scientist or a 
herbalist. However, there is no more reason that there should be a 
one-to-one correspondence between herbal and botanical identifications 
than there is that a word in one language should have a precise equiva- 
lent in another. The sets of characteristics used to delineate species need 
not necessarily be the same in the value system of the herbalist and the 
value system of the botanist. This point might be seen by reference to 
table 2, in which the overlapping of Linnean and herbal names is obvi- 
ous. According to Ford [23], Verbascum thapsus was being sold as gor- 
dolobo in California in 1947. Gordolobo sold in Chicago in September 
1977 was also identified as Verbascum thapsus. When sold in this way, 
Verbascum thapsus is being used as a sore-throat remedy and is consumed 
in the form of a tea. When sold as punchon, it is used to treat asthma. In 
this case, it is either smoked or soaked in whiskey and drunk. Examples 
like this could be multiplied endlessly. 

Furthermore, whereas Linnean names are the lingua franca of botany, 
and are used worldwide, the plants intended to be indicated by a herbal 
name may differ from user to user or region to region in a similar 
manner to the way the common names of plants vary in English. 

In addition to this cultural problem, there are, of course, also prob- 
lems of simple misidentification by people collecting their own herbs. 
Professional herbalists and curanderos (healers) are often extremely 
knowledgeable about the plants they use and can unerringlv select the 
plants they want. Less experienced people, however, in an attempt to 
collect the same material as the herbalist, may collect mixtures of species 
or totally different plants. This explains tragedies, such as one reported 
from Washington state in 1977 in which two people who thought they 
were collecting comfrey (Symphytum) in fact collected foxglove (Digitalis) 
and killed themselves by drinking a tea prepared from it [24]. 

Relationship between Herb Use and Orthodox Medicine 

Kay [8] has described the fundamental place that use of herbs has in 
Mexican and Mexican-American populations. The herbs used are partly 
indigenous, being a holdover of folk customs developed over a long 
period, and partly a vestigial remnant of nineteenth-century European 
medicine. Although these customs have to a large extent died out in 
Europe, they still persist among Mexicans. For example, no Victorian 
book of medicine was complete without a description of chamomile (or 
camomile). This is a herb (Anlhemis nobilis) which has been used since 
Roman times, and in fact was probably imported to England by the 
Romans. The following is a quotation from a four-volume Victorian 



Perspectives in Biology and Medicine • Autumn 1980 1 1 



255 



work on medicine and materia medica (i.e., a reputable book of 
medicine, and not a herbal): "The chamomile is too well known to call 
For anv detailed description" [25]. This comment recalls pre-Johnsouian 
dictionaries in which a dog is defined as an animal too common 10 re- 
quire description. The quote continues: "It grows wild in many parts of 
England, and is a common object in almost every cottage garden," and 
recommends the plant for female complaints, teething, diarrhea, 
cramps, and as a sedative. 

AnUiemis species, such as/f. cotula, are widely sold as herbal teas in the 
Southwest under the European name of chamomile or the Mexican 
name of manzanilla. It is also known as mayweed or dog fennel. It is 
frequently given to babies or young children and is used for teething 
disorders. 

In excess of 600 species of plants are imported into Arizona for sale as 
herbs. Many of these, and the uses they are put to, would be unrecogniz- 
able to a last-century physician. Many others, however, would be readily 
recognized. Some of the plants which are listed both in nineteenth- 
century texts on pharmacy and materia medica and in Mexican herb 
stores are Arnica, calumba (Cocculus palmalus), gentian, Lobelia, mallow 
("marshmallows," candy flavored with mallow — Althaea officinalis — was a 
common confection in England when I was growing up in the fillies), 
quassia chips (Picraena), and sarsaparilla (Smilax). Many other examples 
of the endurance of nineteenth-century European pharmaceutical prac- 
tices among Mexicans could be quoted. 

Public Health Aspects of Herbal-Tea Consumption 

The use of herbs appears to fall into a regulatory hole. They are not 
foods, and they are not drugs. There is no enforced requirement for 
demonstrations of efficacy or safety. This contrasts sadly with reg- 
ulations applied to the drug industry. Any new drug has to undergo 
expensive and time-consuming tests, first to show that it will do what the 
manufacturer claims it will and second to show that it will do this 
safely — and that side effects fall within acceptable limits. No such tests 
are required to introduce a herb. 

Does this lack of regulation indicate a serious public health problem? 
In the absence of detailed information, this is a hard question to answer. 
In cultures that have a tradition of herbal usage, such as Mexican- 
Americans or various American Indian groups, people are in general 
protected from plants that are obviously toxic because the community 
builds up a body of information on these plants. The risk here comes 
from plants — such as those containing pyrrolizidines — in which the toxic 
consequences do not follow immediately upon exposure to the plant. 



1 2 Ryan J. HiixtabU ■ flrrhal Tfns ami Toxin.* 



256 



Recently, there has been a tremendous interest in the use of herbs by 
groups lacking a cultural tradition of plant usage. This results in many 
poisoning cases each year. This may be because of misidentification, as in 
the case of the foxglove tea [24] or with a recent death due to drinking 
Datura by a group on a desert survival exercise. Death or illness may also 
result from the deliberate ingestion of a toxic plant in order to experi- 
ence the disturbance of the central nervous system. Datura stramonium is 
commonly used for this purpose in the Southwest. In many cases of 
poisoning, the herb was purchased from a health-food store, as with 
recent intoxications for pennyroyal, pokeweed, lobelia, burdock, aloes, 
senna, buckthorn, and many other plants (e.g., see [26]). 

APPENDIX 



BIBLIOGRAPHY OF HERBS 

This brief list provides further reading on various aspects of herbs. 

Hedkick, V. P. Slurtevants Edible Plants of the World. New York: Dover, 1972. 

(Originally published 1919.) 
Mili-spaugh, C. F. American Medicinal Plants. New York: Dover, 1974. (Originally 

published 1892.) 
Morion, J. D. Major Medicinal Plants: Botany, Culture and Uses. Springfield, 111.: 

Thomas, 1977. 
Swain, T. (ed.). Plants in ike Development of Modern Medicine. Cambridge, Mass.: 

Harvard Univ. Press, 1972. 
Thomson, W. A. R. Medicates from the Eurth: A Guide to Healing Plants. New York: 

McGraw-Hill, 1978. 
Wheelwright, E. G. Medical Plants and Their History. New York.: Dover, 1974. 



REFERENCES 

1. Bull. L. B.; Culvenor, C. C. J.; and Dick, A. T. The Pyrroliudine Alkaloids. 
Amsterdam: North-Holland, 1968. 

2. Mattocks, A. R. Toxicity of pyrrolizidine alkaloids. Nature 217:723-728, 
1968. 

3. Mohauuat, O.; Siiakic Younos, M.; Mekrao, A. A.; et al. An outbreak of 
hepatic veno-occlusive disease in north-wesiern Afghanistan. Lancet, pp. 
269-271, 1976. 

4. Tan i>on, B. N.; Tandon, R. K.; Tanoon, J. D.; el al. An epidemic of veno- 
occlusive disease of liver in central India. Lancet, pp. 271-272, 1976. 

5. Watt. J. M.. and Bkeyer-Brandwijk, M. G. Medicinal and Poisonous Plants oj 
SouUiern and Eastern Africa, 2d ed. Edinburgh: Livingstone, 1962. 

6. Bras, G.; Jellike, D. B.; and Stuart, K. L. Veno-occlusive disease of liver 
with non-portal type of cirrhosis occurring in Jamaica. Arch. Pathol. 
57:285-300, 1954. 

7. Hill, K. R. The vomiting sickness of Jamaica: a review. West Indian Med. J. 
1:243-261. 1952. 



Perspectives m Biology and Medicine • Autumn 1980 13 



257 



8. Kay, M. A. Health and illness in a Mexican-American barrio. In Ethnic 
Medicine in the Southwest, edited by E. H. Spicer. Tucson: University of 
Arizona Press, 1977. 

9. McGee.J. O. D.; Patrick, R. S.; Wood. C. B.: et al. A case of veno-occlusive 
disease of the liver in Britain associated with herbal tea consumption. J. Clin. 
Pathol. 29:788-794. 1976. 

10. Sherlock, S. Portal hypertension. In Progress in Liver Disease, edited by H. 
Popper and F. Schaffer, vol. 1. London: Heineman, 1961. 

1 1. Lyford. C. L.; Vercara, G. G.; and Moeller. D. D. Hepatic veno-oct lusive 
disease originating in Ecuador. Gastroenterology 70:105-108, 1976. 

12. Deinzer, M. L.; Thomson. P. A.; Burgett, D. M.; et al. Pyrrolizidine 
alkaloids: their occurrence in honey from tansy ragwort (Senecio jacobea 
L.). Science 195:497-499, 1977. 

13. Dickinson, J. O.; Cooke, M. P.; King, R. R.; et al. Milk transfer of pyr- 
rolizidine alkaloids in cattle. /. Am. Vet. Med. Assoc. 169:1 192-1 196. 1976. 

14. Stillman. A. E.; Huxtable, R.; Consroe. P.; et al. Hepatic veno-occlusive 
disease due to pyrrolizidine poisoning in Arizona. Gastroenterology 73:349- 
352, 1977. 

15. Adams, R.; and Govindachari, T. R. Senecio alkaloids: a and /3-longiIobine 
from Senecio longilobus./. Am. Chem. Soc. 71:1 180-1 186, 1949. 

16. Huxtable. R.; Stillman, A.; and Ciaramitaro, D. Characterization of 
alkaloids involved in human Senecio (pyrrolizidine) poisoning. Proc. West. 
Pharmacol. Soc. 20:455-459. 1977. 

17. Fox, D. W.; Hart, M. C; Berceson, P. S.; et al. Pyrrolizidine (Senecio) 
intoxication mimicking Reyes syndrome. J. Pediatr. 93:980-982. 1978. 

18. Kearney, T. H., and Peebles, R. H. Arizona Flora. Berkeley: Univ. Califor- 
nia Press, 1964. 

19. Felcer, R. S.; and Moser, M. B. Seri Indian pharmacopoeia. Econ. Bol. 
4:414-436, 1974. 

20. Huxtable, R.; Paplanus, S.; and Laucharn, J. The prevention of 
monocroialine-induced right ventricular hypertrophy. Chrst 7IS:308-310, 
1977. 

21. Huxtable, R.; Ciaramitaro, D.; and Eisenstein. D. The effect of n pyr- 
rolizidine alkaloid, monocrotaline, on the biochemical functions of the pul- 
monary endothelium. Mol. Pharmacol. 14:1189-1203, 1978. 

22. Hill, K. R.; Rhodes. K.; Stafford. J.L.; et al. Liver disease in Jamaican 
children (serous hepatosis). West Indian Med. J. 1:49-63, 1951. 

23. Ford, K. C. Las yerbas de ia gente: a study of Hispano-American medicinal 
plants. Museum Anthropol. Ser. no. 60. Univ. Michigan. 1975. 

24. Cooper. L.; Grunenfelder. G.; Bi^ckmon. J.; et al. Poisoning associated 
with herbal teas— Washington. Morbidity Mortality Weekly Rep. 26:257-258, 
1977. 

25. Anonymous (Physicians and Surgeons of the Principal London Hospitals). 
The Family Physician: A Manual of Domestic Medicine. London: Cassell, 1884. 

26. Anonymous. Toxic reactions to plant products sold in health food siores. 
Med. Utter 21:29-31. 1979. 



1 4 J Ryan J. Huxtable ■ Herb il Teas and Toxins 



258 

10 

The Toxicology of Alkaloids in 
Foods and Herbs 

Ryan J. Huxtable 

University of Arizona, Tucson, Arizona 



I. INTRODUCTION 238 

n. MISIDENTIFICATION OF A PLANT SPECIES 240 

m. STEROIDAL ALKALOIDS 241 

IV. AN ISOQUINUCLIDINE 243 

V. PYRROT JZTPINE ALKALOIDS 243 

A Symphytum Alkaloids 245 

B. Senecio Alkaloids 248 

C. Crotalaria Alkaloids 249 

D. Heliotropium Alkaloids 250 

E. Tnchodesma Alkaloids 250 

F. Thresholds for Pyrrolidine Alkaloids 250 

VL TROPANE ALKALOIDS 252 

VEL METHYLXANTHINES 253 

Vm. ERGOT ALKALOIDS 255 

DL OTHER ALKALOIDS 256 

X. PRINCIPLES FOR INVESTIGATION OF HERBAL 

POISONINGS 256 

XL ACKNOWLEDGMENT 257 

References 257 



237 



259 

238 Huxtable 

I. INTRODUCTION 

Alkal oids are nitrogenous secondary metabolites found in plants. Typically, 
they are formed from amino acids by decarboxylation plus other modifications 
or derived, in part, from acetate or mevalonate. In many cases, they form part 
of the chemical defense system of the species elaborating them. Alkaloids show 
great structural variation, particularly among the angiosperms, or flowering 
plants. There are estimated to be around 500,000 flowering plant species. This 
is a highly successful group, having evolved in the presence of grazing and 
browsing animals, insect pests, parasites, and bacteria, that owes its success 
largely to its chemical ingenuity. Unsurprisingly, many of the alkaloids 
elaborated by angiosperms and other plants have marked pharmacological 
actions on humans. Alkaloids of therapeutic importance include morphine, 
vincristine, vinblastine, quinine, atropine, cocaine, pilocarpine, reserpine, col- 
chicine, and a host of others. 

About 40% of plant families contain alkaloid-bearing plants, although 
alkaloids are present in only around 9% of genera. In a given species, alkaloid 
content can vary widely, depending on the part of the plant, its maturity, the 
time of year, geographic location, and type of soil. Even plants examined from 
the same location at the same time of the year can show wide variations in 
alkaloid content from one year to the next. Thus, Senecio longilobus leaves 
show an 80-fold variation in alkaloid content, and S. riddellii a 100-fold varia- 
tion (Johnston et al., 1985). Storage conditions can also markedly affect 
alkaloid content. With potatoes, for example, a 50-fold increase in alkaloid level 
m-n occur on inappropriate storage (Sharma and Salunkhe, 1989), while con- 
versely alkaloid levels in certain Crotalaria species can decrease on storage 
(Heath et aL, 1975). 

When alkaloids are taken by mouth, toxicity can be expressed in the 
gastrointestinal tract. In certain cases, however, bioactivation in the liver is 
required for toxicity. In such cases, gastrointestinal toxicity is minimized, 
toxicity, instead, being expressed in the liver, the lungs (which receives the 
brunt of substances leaving the liver), and the kidneys, in which alkaloids and 
metabolites may be concentrated and excreted. Fetuses and neonates lack 
bioactivating enzymes such as the mixed function oxidases, and therefore tend 
to accumulate alkaloids, such as caffeine (see Fig. 6), which depend on metab- 
olism for excretion. Hence, while the half-life of caffeine in adults is 4.9 * 1.8 h, 
in full-term babies it is 80 * 26 h, and in premature babies 102.9 * 17.9 h 
(Aldridge et al., 1979; Dews, 1984). Neonates may also show less susceptibility 
to the toxicity of alkaloids requiring bioactivation. However, other factors also 
affect the response of the developing organism to alkaloids, so generalization is 
dangerous. 

Depending on their lipid solubility, alkaloids can exhibit central nervous 
system toxicity. Lipid solubility is also a function of the basicity of an alkaloid. 
The higher the pKa, the higher the fraction of alkaloid that is ionized at 
physiological pH, and the lower the partition coefficient into lipid compart- 
ments, such as the brain (Fig. 1). The central nervous system effects are often 
the primary reason alkaloids are intentionally taken, other than for medical 



260 



Toxicology of Alkaloids 

100 



239 



'c 
o 



o 

c 



50 




ipopnilic 



pH 

Rgure 1 Pharmacokinetic relationship between the pKa of an alkaloid and its ability to 
penetrate the brain. The more basic the alkaloid, the higher the value of the pK« 
relative to physiological pH, and the greater the fraction of the alkaloid in the body in 
the ionized, conjugate acid, form, and the lower the fraction in the lipophilic form. 



reasons. The use of caffeine in the form of coffee or tea, nicotine (see Fig. 6) in 
the form of tobacco, or, in various forms, of cocaine (see Fig. 6), morphine, and 
a host of other alkaloids is predicated on their central actions. 

Hepatic metabolism typically consists of hydroxylation and conjugation. In 
general, hepatic metabolites have increased aqueous solubility and lower lipid 
partition coefficients than the parent alkaloid, and thus are likely to have less 
effect on the central nervous system. These characteristics also hasten excre- 
tion from the body. 

Many alkaloids, such as coniine (see Fig. 6), nicotine, cocaine or tropane 
alkaloids such as scopolamine or atropine (see Fig. 6) are readily absorbed 
across mucous membranes or through the skin. Hamlet's father was frater- 
nally murdered by means of a plant extract being poured into his ear as he 
slept. The plant has been tentatively identified as Conium maculatum, a source 
of coniine (Max, 1988). Such alkaloids can be absorbed directly from the oral 
cavity or by the lungs, if inhaled. 

Alkaloids tend to be bitter-tasting and to have marked pharmacological 
actions. They, therefore, are rarely consumed intentionally in foods. Exceptions 
include the monoamines, such as tyramine, present in cheese and beer. Where 
contamination of food occurs, this is often evident from the taste. Alkaloid- 
containing plants, on the other hand, are frequently taken as medicines or 
herbs or for their psychoactive effects. These are perhaps loose statements, as 
the division between herbs, food, and medicines is often blurred, the words 



261 



240 Huxtable 

having no precise scientific meaning, although they may have precise legal 
meanings. The concepts are not exclusionary. Few would think of a cup of Earl 
Grey tea made with sugar and milk or cream as being a medicine, but tea is 
psychoactive, one of the great writers of the twentieth century describing it as 
"the reviewing brew." To give someone a sweetened cup of tea is one of the great 
British panaceas. Early Grey is the infusion of the leaves of one herb, Camellia 
sinensis, flavored with the extract of another herb, the carcinogenic bergamot 
(Citrus aurantium). Earl Grey is certainly nutritious, especially if the con- 
sumer had opted for the cream rather than the milk. So this common beverage 
partakes of the qualities of all three of the categories listed. The uses of 
alkaloid-containing plants as foods, herbs, remedies, or recreation thus blend 
into each other. 

People can be affected by alkaloids in the foods or herbs they use for a 
number of reasons: intentionally, if a plant is ingested for the pharmacological 
properties of the alkaloids it contains, as with coffee, khat, peyote or tobacco; or 
accidentally (Huxtable, 1990a). Accidental exposure to alkaloids can occur 
because of food contamination; because an alkaloid-containing plant was taken 
deliberately without the consumer being aware of the danger, or because a 
misidentified plant was consumed. 

There has been a marked and continuing increase in the number of 
alkaloid-containing plants sold as teas, herbs, herbal remedies, food additives, 
and food supplements in North America. Of the 200 species Siegel reported as 
being sold as smoking mixtures and the 400 species being sold as teas or food 
supplements, many were alkaloidal (Siegel, 1976). The species included 
Corynantheyohim.be (yohimbine), Cola spp. (methylxanthines), Lobelia inflata 
(lobeline), Argemone mexicana (berberine), Nicotiana spp. (nicotine), Ilex 
paraguayensis (caffeine), Ephedra spp. (pseudoephedrine or ephedrine, 
depending on whether the plant derives from the New World or Old), Passiflora 
incarnata (harmine alkaloids), Catharanthus roseus (indoles), Rauwolfia ser- 
pentina (reserpine), and Datura spp. (tropane alkaloids). At least in the United 
States, these substances are largely unregulated; if they are not sold as food or 
drugs, but as food additives, food supplements, or herbal remedies, they escape 
regulation by the Food and Drug Administration An indication of the kind of 
public health problems associated with the widespread use of herbs is a 
Swedish study showing a correlation between herb use and hepatitis (Carlsson, 
1990). Liver function tests normalized in 52 of 53 patients when herb use was 
stopped for 6 weeks. 

II. MISIDENTIF1CATION OF A PLANT SPECIES 

Commercially sold plants are not infrequently misidentified. Atropa bella- 
donna (deadly nightshade) has been sold as comfrey (Symphytum species) 
(Anonymous, 1983; Galizia, 1983; Routledge and Spriggs, 1989). Tropane 
alkaloid poisonings, probably as a result of contamination with Atropa species, 
have occurred following the consumption of plants purporting to be burdock, 
comfrey, mallow, and nettle (Awang and Kindack, 1989). A death was reported 
in England of a person supposedly drinking mate (Ilex paraguayensis), but 



262 



Toxicology of Alkaloids 241 

which, judging from the clinical picture, was probably in fact a pyrrolizidine- 
containing species (McGee et al., 1976). In the western United States, two 
species of Compositae, Senecio longilobus and Gnaphalium macounii, had been 
commercially sold under the same herbal name, gordolobo yerba, for many 
years. The Senecio species is toxic, and has been responsible for a number of 
deaths and illnesses (Stillman et al., 1977; Fox et aL, 1978; Huxtable, 1980a). 
Gnaphalium is apparently nontoxic Some believe the two plants may have 
been confused, due to their similar phenotype. 

Misidentification can also occur in self-collected, or noncommercially col- 
lected, plants. Digitalis is frequently mistaken for comfrey (Symphytum), with 
deaths resulting (Cooper et al., 1977; Dickstein and Kunkel, 1980; Bain, 1985). 
A team on a desert survival course it southern California became ill, one 
member dying, after a salad was prepared from a Datum species (jimsonweed), 
mistaken for an innocent species (Huxtable, 1980a). 

III. STEROIDAL ALKALOIDS 

Among the numerous botanical gifts of the New World to the Old were the 
tomato and the potato. These two solanaceous species have become so 
embedded in the cuisines of Europe and their derivatives around the world that 
the one is as inseparable from Italian pasta as the other from the Englishman's 
meat and two veg. Worldwide, 300 million tons of potatoes (Solanum 
tuberosum) and 20 million tons of tomatoes (Lycopersicon esculentum) are 
consumed yearly. Potato production worldwide is exceeded only by that of 
wheat and rice (Harvey et al., 1985). In the United States, the consumption of 
tomatoes ranks second only to that of potatoes. For 1970, U.S. production of 
potatoes was 16.3 million tons and of tomatoes 6.0 million tons. Sweet corn was 
a poor third among edible plants at 2.5 million tons (Jadhav et al., 1981). 
Despite the world's appetite for the tomato and the potato, these two 
solanaceous species, along with many others in their family (Kingsbury, 1964), 
contain alkaloids that are severely toxic above a certain level. 

The major alkaloids in potato are a-solanine and a-chaconine (Fig. 2), 
steroidal glycosides differing only in their glycoside composition. These two 
alkaloids constitute around 95% of total alkaloid content (Harvey et al., 1985). 
Alkaloids are found in all parts of the potato plant, but concentrations are 
highest in unripe, green potatoes, damaged potatoes, and potatoes stored 
inappropriately. Light exposure also increases the level of alkaloids, which, 
past a certain point, produce a bitter or musty taste in the potato (Jadhav 
et aL, 1981; Dalvi and Bowie, 1983). The control of potato alkaloids includes 
avoiding mechanical damage and protecting potatoes form light by means of 
colored bags. 

The approximate concentrations of alkaloids found in various parts of the 
potato plant are (mg/100 g fresh weight): flowers, 300-500; sprouts, 200-400; 
leaves, 40—100; skin, 30-60; and flesh, 1.2—5. However, concentrations vary 
widely among the enormous number of cultivars that have been developed. 
Assays of 165 samples in Sweden showed alkaloid levels ranging from 2 to 30 
mg/100 g (Johnsson and Hellenas, 1983). Other studies showed ranges of 



263 



Huxtdble 




•CH 3 



XVDM 

Glucose-Galacios*- 

I 

Glucose 




(b) 



Figure 2 Steroidal alkaloids of the Solanaceae: (a) a-solamne [R -D-galactose- 
(D-giucoBe)-L-rhamose] and a-chaconine [R: -D-gluco9e-(L-rhamnose)-L-rhamnose] 
from potatoes (SoUmum tuberosum), and (b) a-tomatine from tomatoes (Lycopersicon 
esculentum). 



4.6-3.5 mg/100 g in 39 cultivars, 1.8-13 in 32 cultivars, and 1.9-7.6 in 15 
cultivars (see Sharma and Salunkhe, 1989). Levels in fresh tubers can vary 
10-fold. As well as genetic differences, geographic differences produce differing 
alkaloid levels in the same strain. The alkaloids appear to be involved in 
disease and insect resistance Damaged or poorly stored potatoes can contain 
up to 160 mg alkaloids/100 g (Sharma and Salunkhe, 1989). 

Given an average level of 2—5 mg alkaloid/100 g potato tuber, world con- 
sumption of potato alkaloids is somewhere in the range of 5-14 x 10 6 kg per 
annum (5500-15,400 tons). Alkaloid content is not appreciably reduced by 
cooking or steeping in water, as the alkaloids are insoluble. A major action of 
the alkaloids is that of cholinesterase inhibition. They are also cardiotonic, 
having digitalislike actions. In addition, there are repeated, disputed, claims 
that these alkaloids are teratogens (Ames, 1983). Doses in excess of 2-8 mg/kg 
produce hyperesthesia and drowsiness. Higher doses cause vomiting and diar- 
rhea. Numerous cases of poisoning from potato alkaloids are known. These 



264 



Toxicology of Alkaloids 243 

have been reviewed (McMillan and Thompson, 1979; Jadhav et al., 1981). A 
typical case involved 78 boys at a London school who fell ill after lunch 
(McMillan and Thompson, 1979). Seventeen were admitted to hospital. The 
steak pie, gravy, cabbage, tinned carrots, syrup sponge pudding, and custard 
were all eliminated as suspects, leaving the mashed potato. An extract of th\* 
was found to inhibit cholinesterase activity. 

It is normally assumed that potatoes with alkaloid levels below 20 mg/100 g 
fresh weight are safe for consumption (Johnsson and Hellenas, 1983). How- 
ever, the ratio between levels at which toxicity has been observed and levels 
deemed for human consumption is rather low. Also, study subjects given 
potatoes containing 20—30 mg alkaloid/100 g daily for a week showed no ill 
effects (Harvey et al., 1985). This has led to suggestions that other factors may 
be involved in potato poisoning. Potato alkaloids are normally poorly absorbed 
from the gastrointestinal tract. It is possible that an increase in alkaloid 
content is associated with an increase in related steroidal saponins or 
sapogenins and that these may increase the degree of absorption of the 
alkaloids. People with atypical serum cholinesterase are less susceptible to 
cholinesterase inhibition than people with typical activity. There could, there- 
fore, also be a genetic component in potato toxicity. 

A related alkaloid is found in tomatoes and has been christened a-tcmatine 
(Fig. 2) (Jadhav et al., 1981). This triglycoside is found in all parts of the plant, 
being particularly high in leaves. Here the levels may be 10-50 times the level 
in the fruit. Analogous to the potato, levels fall as the fruit ripens. Tomatoes 
left on the vine after ripening lose almost all their alkaloid within 2-3 days. 
Artificially ripened fruit, however, the kind available at your local super- 
market, contain higher levels. 

Other solanaceous species, such as eggplant (Melongena), also contain 
steroidal alkaloids (Dalvi and Bowie, 1983). 

IV. AN ISOQU1NUCUDINE 

Yams (Dioscorea spp.) are another group of solanaceous plants comprising a 
major food source, in this case for tropical countries. Worldwide production is 
about 20 million tons per annum (Jadhav et al., 1981). In certain West African 
communities, yams may supply half the calories. Many wild species are highly 
toxic due to their content of isoquinuclidine alkaloids such as dioscorine 
(Fig. 3). This alkaloid, which has convulsant, picrotoxinlike effects on the 
central nervous system, can be partially removed by soaking and leaching the 
yams in water. 

V. PYRROLIDINE ALKALOIDS 

Pyrrolidine alkaloids are abundant in the plant kingdom. It has been esti- 
mated that about 3% of all plants contain such alkaloids (Smith and Culvenor, 
1981). They have been isolated from more than 60 genera in at least 13 
families. PyTrolizidines are major causes of human and animal poisoning, 
partly because of their geographical and botanical ubiquity, and partly because 



265 



244 Huxtable 




Figure 3 Dioscohne, a major alkaloid in yams (Dioscorea spp.). 



of the chronic and cumulative nature of pyrrolizidine toxicity (Huxtable, 
1980b). PyTTolizidine-containing plants are frequently used as herbs, 
vegetables, and dietary supplements (Huxtable, 1990a). Contamination of 
grains with the seeds of pyrrolizidine-containing plants has on a number of 
occasions produced epidemics of pyrrolizidine poisoning (Huxtable, 1989a). 

1,2-Unsaturated pyrrolizidine alkaloids produce veno-occlusive disease of 
the liver as a consequence of bioactivation in that organ (Huxtable, 1979, 
1990b). Such disease is highly characteristic of pyrrolizidine poisoning, its only 
other known occurrence being a consequence of chemotherapy with drugs 
related to cytarabine. The three stages of veno-occlusive disease are shown in 
Figure 4. An acute phase of hepatomegaly and ascites may either resolve or 
progress to the subacute phase. In the chronic phase, cirrhosis of the liver 
develops (Huxtable, 1989a). As cirrhosis is a late consequence of exposure, even 
a large contribution of pyrrolidines to the incidence of cirrhosis in a popula- 
tion will not be recognized unless specifically looked for. 

Certain pyrrolizidine alkaloids, such as the Crotalaria alkaloids, monocro- 
taline and fulvine (Fig. 5), also cause pulmonary arterial hypertension and right 
ventricular hypertrophy in experimental and farm animals. Other pyrrolizidine 
alkaloids are teratogenic (Green and Christie, 1967; Peterson and Jago, 1980). 

Finally, many pyrrolizidine alkaloids are carcinogenic. These include 
alkaloids from plants that are widely consumed, such as those of the Senecio, 
Petasites, Tussilago, Crotalaria, and Symphytum genera (Green and Christie, 
1967; Bull et aL, 1968; McLean, 1970; IARC, 1975; Mattocks, 1986). The high 
rate of primary liver cancer in South Africa has been ascribed to chronic low 
level exposure to pyrrolizidines (Schoental, 1968). 

Epidemics of pyrrolizidine poisoning have occurred in many parts of the 
world. Genera implicated have been Heliotropium, Trichodesma, Senecio, and 
Crotalaria. The largest documented outbreak occurred in Afghanistan, affect- 
ing some 7200 people as a result of grain being contaminated with the seeds of 
Heliotropium popovii (Mohabbat et aL, 1976). Some 2000 people died. Other 
outbreaks have occurred in India, Uzbekistan, South Africa, and the Caribbean 
nations (Huxtable, 1989a). Estimations of doses have proved difficult. For the 
Afghanistan outbreak, consumption levels of 2 mg/day for periods of up to 2 
years have been estimated. It appears that contamination of food grains is most 
likely in arid climates in areas with poor irrigation facilities, weak regulations, 



266 



Toxicology of Alkaloids 



245 



Comoiete 
recovery (*8%) 



Clinical 
recovery (20%) 



'Latent period ot years 



Acute veno-occiusive 
disease 
(sudden heoatomegaly 
and ascites) 



(13*) 



Suoacuie veno-occlusive 

disease 

(persistent lirm neoatomegaly) 



Chronic veno-occlusive 

disease 
(cirrnosis ol liver) 



Raoid deatn ( 19%) 
(increasing /aundice 
cnoiemia) 



Clinical imorovement 



Comolete recovery 



Figure 4 The major stages of veno-occlusive disease induced by pyrrolizidine alkaloid. 
(Adapted from Stuart and Bras, 1957.) 



and underdeveloped health services, i.e., areas of the world where most of the 
population resides (United Nations, 1988). 

Reports of veno-occlusive disease are legion It can be safely assumed that the 
majority of these indicate exposure to a dietary source of pyrrolizidine alkaloids. 
Many of these reports have been recently summarized (Huxtable, 1989a). 

Pyrrolizidine-containing plants are widely consumed in various forms all 
over the world. In Africa, for example, the use of Senecio gigas in Ethiopia has 
been associated with the development of ascites (Watt and Breyer-Brandwijk, 
1962). Many Crotalaria species are used throughout Africa. In Japan, Tus- 
silago farfara is commonly consumed under the name kan-to-ka, despite its 
known carcinogenicity due to its senkirkine content (Fig. 5) (Hirono et al., 
1976, 1979). Other pyrrolizidine-containing plants consumed in North 
America, Europe, or Japan include Petasites japonicus Maxim, Farfugium 
japonicum, and Senecio cannabifolius (United Nations, 1988). However, the 
speed and volume of travel, and the mass migration of peoples who take 
customs and culture with them make the world a unity in terms of exposure to 
pyrrolizidines. Alkaloid poisoning has occurred in the United States following 
the consumption of teas imported from Europe and Asia, and pyrrolizidine 
poisoning has occurred in Europe following the use of teas imported from South 
America. 

A. Symphytum Alkaloids 

Symphytum (comfrey) species present a particular problem. Symphytum 
species are grown commercially in Europe, North America, Japan, and 



267 



246 



Huxtable 



CH 3 CH 3 





(a) 



(b) 



H,C 




CH 2 OR 2 




(c) 



(d) 



R,0 Me 

Me ? H 



R : -C-C-OH 

I I 
Me C0 7 H 

(e) 



Figure 5 A selection of pyrrolidines: (a) monocrotaline (Ry. CH3, R2; OH, R3: OH); 
fulvine (Ry. CH3, R2: OH R3: H); trichodesmine (Ry. (CH3>2CH R2: OH, R3: OH); 
incanine (Rl: (CH3)2CH R2: H, R3: OH); (b) retrorsine (Ri: CH3, R2: CH2OH); 
senecionine (Ri: CH3, R2: CH3); (c) echimidine (Ry. angeloyl [c«-2-methyl-2-butenoyl], 
R2: echimidinoyl); symlandine (Ry. angeloyl, R2: viridifloroyl); symphytine (Ry. tisloyl 
[2-methyl-but-2-enoyl], R2: viridifloroyl); heliotrine (Ry. H, R2: trachelanthoyl); 
(d) senkirkine. Esterifying acids: angelic CH3CH:C(CH3)COOH; (e) echimidinic (Ry. H, 
R2: OH), trachelanthic and viridifloric (stereoisomers of (e) at the position indicated by 
*, Ri: H R2: H). 



Australia (Furuya and Araki, 1968), and are widely consumed in the form of 
vegetables, salads, herbal teas, and herbal remedies, even though they have 
long been known to contain hepatotoxic and carcinogenic pyrrolizidine 
alkaloids (Svoboda and Reddy, 1972; Hirono et al., 1979, 1978; Culvenor et al., 
1980). Confusion between the hybrids and species of Symphytum is frequent 
(Huxtable and Awang, 1970). There are at least 25 species of Symphytum. 
Common comfrey is S. officinale. The literature has been confused by the use of 



268 



Toxicology of Alkaloids 247 

the term Russian comfrey to refer to S. officinale (Hiroiio et aL, 1978). This 
term is correctly associated with S. asperum or its hybrids, such as S. x 
uplandicum Nym. The detection of the pyrrolizidine alkaloid, echimidine 
(Fig. 5), in a sample indicates the presence of S. asperum. or its hybrids 
(Culvenor et al., 1980). Echimidine is significantly more toxic than other com- 
frey alkaloids (Mattocks, 1986). Inaccurate botanical labeling is common for 
herbal products and is not limited to Symphytum. 

Alkaloid content of Symphytum can vary widely. Leaves can contain 
between 30 and 1150 mg/kg of alkaloid, with young leaves containing more 
t h«r> old (Mattocks, 1980). Roots contain considerably more alkaloid than the 
leaves. S. asperum roots contain between 1400 and 4000 mg/kg alkaloid 
(Roitman, 1981). Depending on the material and its preparation, Roitman 
(1981) has calculated that up to 26 mg of pyrrolizidine alkaloids per cup of 
comfrey tea could be consumed. 

The safety of Symphytum has been a contentious issue between scientists 
and the herb industry. It is true that the number of documented cases of 
Symphytum poisoning is low. Acute toxicity is low. Thus, in rats, the acute 
LD50 for mixed Symphytum alkaloids has been determined to be around 550 
mg/kg (Culvenor et al., 1980). However, the toxic actions of pyrrolizidines are 
cumulative — the total dose being more important than the length of time it 
takes to reach this dose (Shubat et al., 1989) — and clinical symptoms that 
eventually appear, such as cirrhosis, may be nonspecific and not associated 
with the ingestion of a herb. Furthermore, to find an association requires that 
an association be looked for, and this has yet to be done on any consistent basis 
with pyrrolizidine-containing herbs. Even where a herb is suspected, dose 
calculations are often difficult. It may be impossible to get a sample of the 
actual herb consumed, a sample taken at a given time may not accurately 
reflect the average level of exposure over a longer period (as with the Afghan 
epidemic, in which samples of food were taken on one occasion during the 6 
months to 2 years of exposure), and there may be difficulty in getting estimates 
of how much contaminated food was consumed, how often, and over what 
period of time. In an outbreak of veno-occlusive disease in India, poor correla- 
tion was found in the affected villages between the pyrrolizidine content of 
grain in households and the presence of veno-occlusive disease in the 
household; i.e., the sample of grain taken was not truly representative of the 
family's exposure over a period of time (Tandon et al., 1976; Krishnamachari 
et al., 1977; Arora et al., 1981). The true incidence of pyrrolizidine poisoning is 
probably orders of magnitude greater than the established cases (Culvenor 
et al., 1980). 

Several cases of comfrey poisoning have been described (Ridker et al., 1985; 
Weston et al., 1987; Abbott, 1988; Bach et al., 1989; Huxtable, 1989a; Jones 
and Taylor, 1989; Yeong et al., 1990). A 47-year-old woman developed ascites 
and liver disease after drinking up to 10 cups of comfrey tea per day, and 
consuming comfrey pills in addition, over a period of 1 year (Bach et al., 
1989). A 13-year-old boy given comfrey root and comfrey leaf tea for the 
supposed treatment of Crohn's disease developed ascites and hepatomegaly 
(Weston et al., 1987). A 49-year-old woman suffered portal hypertension and 



269 



248 Huxtable 

veno-occlusive disease after taking comfrey-pepsin capsules daily for 6 months 
(Ridker et al., 1985). A 23-year-old man, a vegetarian, died of veno-occlusive 
disease in New Zealand after eating comfrey leaves over a period of time 
(Yeong et aL, 1990). 

In the United States, a major source of exposure to Symphytum alkaloids is 
the widespread use of comfrey-pepsin capsules as digestive aids. Typically, 
these are consumed with each meal. Some brands are prepared from Sym- 
phytum root and some from leaves, although frequently no information is given 
as to the source. Alkaloid content varies widely (Huxtable et al., 1986). 
We have, for example, found one preparation with a total alkaloid content of 
270 mg/kg and another containing 2900 mg/kg (Huxtable et al., 1986). In 
both cases, the alkaloids found were symphytine and symlandine (Fig. 5), 
and the isomeric pairs, 7-acetylintermedine plus 7-acetyllycopsamine and in- 
termedine and lycopsamine. Analysis of one batch of comfrey-pepsin capules 
being taken by an elderly woman with veno-occlusive disease, portal hyperten- 
sion, and cirrhosis showed a pyrrolizidine content of 988 mg/kg (Huxtable, 
1989a). As each capsule contains 500-600 mg of the preparation, and as 
numbers of capules are consumed daily for periods of months, comfrey-pepsin 
capsules are clearly a major source of exposure to carcinogenic and hepatotoxic 
alkaloids. 

B. Senecio Alkaloids 

Senecio is a many-membered, widely distributed genus in the Compositae. In 
excess of 100 Senecio species are known to contain pyrrolidines (Mattocks, 
1986). Despite this, worldwide, there are numerous uses of Senecio as food 
or medicine (Rose, 1972; Mattocks, 1986; Huxtable, 1989a). In Paraguay, 
for example, flower heads of S. grisebachii are added to mate tea. Retrorsine 
(12.7 mg), a highly toxic alkaloid (Fig. 5), has been found in a drink prepared in 
such a manner (Hirschmann and Cespedes, 1986). Retrorsine was also the 
major alkaloid involved in the poisoning of children in Arizona with teas 
prepared from S. longilobus (Huxtable, 1980a). Two cases of veno- occlusive 
disease have been reported from Switzerland following the ingestion of Senecio 
teas (Margalith et aL, 1985). Numerous herbal usages of other pyrrolizidine- 
containing species have been reported (Huxtable, 1989a). 

The first description of pyrrolizidine poisoning of humans involved poison- 
ing with bread contaminated with the seeds of S. ilifolius and S. burchelli in 
South Africa (Willmot and Robertson, 1920). Deaths, primarily of children, 
occurred within 10 days to 2 years of exposure. An alarming aspect of this 
outbreak was that the symptoms of pyrrolizidine poisoning had been known in 
the area for at least 10 years prior to the investigations of Willmot and 
Robertson (1920). Underreporting of pyrrolizidine poisoning is typical, due to 
the unspecific nature of the symptoms (pains in the abdomen, bloating, wast- 
ing), and the chronic nature of the poisoning, symptoms developing gradually 
over a prolonged period. The association with ingestion of pyrrolizidine- 
containing plants is not readily made. Thus, 30 years after the first investiga- 
tion, another series of deaths from Senecio contamination of grain was reported 



270 



Toxicology of Alkaloids 249 

in South Africa (Selzer and Parker, 1950). Again, the investigators report that 
the disease was well known to the population of the district. Fifteen years ago, 
we described pyrrolizidine poisoning as being an iceberg disease, a charac- 
terization we feel is still descriptive (Stillman et al, 1977). Other outbreaks 
of poisoning due to food contamination by Senecio alkaloids are known 
(Al-Hasany and Mohamed, 1970; Rose, 1972). The epidemic of venc-occlusive 
disease in the West Indies that extended from at least the 1930s (and probably 
much earlier) until the early 1960s was caused by consumption of bush teas 
prepared from both Senecio and Crotalaria species. This epidemic has been 
reviewed recently (Huxtable, 1989a). 

Poisonings, including deaths, from the use of commercially available 
herbal teas prepared from S. longilobus have been reported for the United 
States (Stillman et al., 1977; Fox et al., 1978; Huxtable, 1989a). For some of 
these cases, reasonably accurate calculations of consumption could be made. 
One 6-month old girl developed veno-occlusive disease progressing to cirrhosis 
after being fed herbal tea over a 2-week period. The quantity of tea used 
contained about 150 mg pyrrolizidines (primarily retrorsine N-oxide), but when 
tea was prepared according to the recipe used it was found that only about 
70 mg were extracted. A 2-month old boy died after being given a similar herbal 
tea for 4 days. In this case, the amount of alkaloid estimated as having been 
consumed was 66 mg over a 4-day period (Huxtable, 1980a). Other cases 
of poisoning from S. longilobus in the United States have been described 
(Huxtable, 1980a). Poisonings from the use of Senecio teas have been reported 
for other countries (e.g., Margalith et al., 1985). 

Senecio alkaloids are excreted in the milk of animals grazing on S. jacobaea 
and are found in the honey of bees grazing on the same plant. There is a 
possibility that dairy products, meat, and honey may contain traces of these 
alkaloids. 

C. Crotalaria Alkaloids 

Crotalaria species have been frequently used as food plants in various parts of 
the world, including the West Indies and Africa (Huxtable, 1989a). Large-scale 
outbreaks of veno-occlusive disease have been reported from Jamaica due 
to the use of pyrrolizidine-containing Crotalaria and Senecio species in 
so-called "bush teas," commonly used in large quantities to treat various 
childhood ailments (Hill et al., 1951, 1953) (reviewed in Huxtable, 1989a). 
Vigorous public health measures have, apparently, much reduced the incidence 
of veno-occlusive disease in recent years. Similar outbreaks for similar reasons 
have occurred in other countries, including Egypt and India (see Huxtable, 
1989a). 

Contamination of millet seed with the seeds of C. nana has led to epidemics 
of poisoning in India (Tandon et al., 1976; Krishnamachari et al., 1977). In one 
outbreak in Mahya Pradesh, 28 of 67 affected people died. A survey a year later 
found up to 9% of the population of a village suffering from ascites. The 
difference in size between C. nana seeds and the larger millet seeds allow 
winnowing or sieving techniques to be used in cleaning food seed 



271 

250 Huxtable 

D. Heliotropium Alkaloids 

HeUotropium species are used medicinally, herbally, or as foodstuffs in most 
areas of the world (Schoental, 1968; Ford, 1975; Morton, 1981; Mattocks, 1986). 
Their use has been associated with an increased incidence of liver cancer. Thus, 
the higher cancer rates among desert-living Bedouin as compared to their 
town-living relatives may be connected with the consumption of H. ramos- 
sisimium by the former (Schoental, 1982). Poisonings by Heliotropium due to 
contamination of barley have been common in central Asia (cf. McLean, 1970; 
Huxtable, 1989a). The biggest documented outbreak of pyrrolizidine poisoning 
in modern times occurred in the Herat province of Afghanistan. This was 
caused by the consumption of bread prepared from grain contaminated with H. 
popovii (Mohabbat et al., 1976; Tandon et al., 1976). Heliotrine (Fig. 5) was the 
alkaloid primarily responsible. Thousands of people were affected. 

H. eichwaldii is commonly used in Ayurvedic medicine. Deaths have been 
reported from the use of this plant, which may, indeed, contribute significantly 
to the incidence of veno-occlusive disease in India (cf. Huxtable, 1989a). Other 
cases of Heliotropium poisoning have been reported (Tandon et al., 1978; 
Kumana et al., 1983, 1985; Culvenor et aL, 1986). 

E. Trichodesma Alkaloids 

The Trichodesma alkaloids, trichodesmine and incanine (Fig. 5), are closely 
related to monocrotaline. They are, however, much more toxic and are also 
unusual in that they produce neurological damage in humans, if Soviet reports 
are to be credited (Ismailov, 1970; cf. Huxtable, 1998a). An outbreak of 
Trichodesma poisoning occurred in the Samarkand region of Uzbekistan in the 
1950s as a result of contamination of grain. At least 44 people died. 

F. Thresholds for Pyrrolizidine Alkaloids 

No threshold for safe exposure to pyrrolizidine alkaloids has been established 
(United Nations, 1988). However, the levels at which toxicity in humans has 
been documented has drifted steadily downwards over the years as inves- 
tigators become more aware of the delayed and cryptic hazards of these sub- 
stances. It appears that humans are more susceptible to pyrrolizidine poison- 
ing than are rats. Toxicity is exacerbated when repeated small doses are given 
over a period of time. Babies appear to be particularly vulnerable to the 
dangers of low-level exposure, despite their relative deficiency of the liver P450 
mixed function oxidase systems responsible for bioactivating pyrrolizidine 
alkaloids to the toxic, alkylating pyrroles (Huxtable, 1990b). 

An estimate of human toxicity can be obtained by calculating exposures in 
terms of "rat LD50 units." This normalizes exposure in terms of measurements 
on a readily studied species. If this is done for the cases in which estimations of 
consumption are available, the data of Table 1 are obtained. As tenuous as the 
data are, the table suggests that total intake of pyrrolizidine alkaloids to levels 
approximating 0.05-0.1 of the rat LD50 can be toxic to humans. 



272 



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252 Hu xt able 

A minimum daily intake of 15 ug/kg/day of pyrrolizidine alkal oids was 
calculated for a middle-aged woman with veno-occlusive disease (Ridker et al., 
1985). There may have been other, unknown, sources of exposure. This, how- 
ever, compares with the 30 ^g/kg/day calculated for the Afghanistan epidemic 
(Mohabbat et al., 1976), although this estimate has been disputed, and it has 
been claimed that alkaloid intake could have been as high as 1300 mg/day 
(Anderson, 1981). 

If the identification of senecionine (Fig. 5) as the intoxicating agent in the 
Swiss case discussed in Section X is accurate (Roulet et al., 1988), the maxi- 
mum dose the child received in utero could have been no more than 0.125 
mg/kgbody weight, or 0.0025 rat LD50 units (Huxtable, 1989b). Problematic as 
this value is, it is not out of line with the data of Table 1. The high values for 
the S. Iongilobus poisonings (Huxtable, 1989a) are probably a reflection of 
supra-toxic doses being administered to small children over a comparative 
short period of time. 

In one well-investigated case of Heliotropium poisoning of four women 
in Hong Kong, seeds were grown from an herb sample and identified as 
H. lasciocarpum (Kumana et al., 1985). Reliable evidence of total alkaloid 
consumption was obtained in this case, helped by one patient who continued 
taking the herb against medical advice. She died. 

VI. TROPANE ALKALOIDS 

Tropane alkaloids, such as atropine (Fig. 6), scopolamine, or Z-hyoscyamine, are 
found in plants such as Atropa belladonna, Datura stramonium, and 
Hyocyamus niger. Atropine itself is an artefact of isolation, being formed from 
the racemization of Z-hyoscyamine. These plants are consumed as a result of 
commercial contamination of other plants (Awang and Kindack, 1989), 
misidentification or lack of knowledge of their toxicity by persons collecting for 
themselves, and, most frequently, by intentional use of plants for their central 
nervous system action. An accidental poisoning occurred when D. suaveolens 
seeds were added to hamburger (Anonymous, 1984). Occasionally, children are 
poisoned through eating Datura berries (Taha and Mahdi, 1984). Cases on 
poisoning following intentional consumption of Datura species, commonly 
called jimsonweed or moonflower, are legion (e.g., Urich et al., 1982 and refer- 
ences therein). A single Poison Control Center in the United States has 
reported 73 cases of intentional ingestion of Datura in a 5-year period (Klein- 
Schwartz and Oderda, 1984). Jimson is a corruption of Jamestown, the name 
referring to a mass intoxication by Datura in that Virginian town in 1676, 
when those who consumed it "turned fools upon it for several days" according 
to one early author. This is in keeping with Shakespeare's description of 
A. belladonna as "the insane root which takes the reason prisoner." Tropane 
alkaloids are anticholinergic, and toxicity is primarily a consequence of this. 
The intoxicated individual is described in mnemonic phrases as hot as a hare, 
dry as a bone, blind as a bat, mad as a hatter, red as a beet. 

D. stramonium is sold as an asthma medication, and poisdnings have 
frequently occurred as a result (Feenaghty, 1982). All parts of the plant are 



274 



Toxicology of Alkaloids 



CHjOH 
I 
OCOCHC 6 H s 




H,C 



N 

I 
CH3 

(a) 




H 3 C0 2 C 




(c) 




CH2CH2CH2 



(d) 




(e) 



Figure 6 (a) Atropine from jimsonweed (Datum spp.) and deadly nightshade (Atropa 
belladonna); (b) caffeine from coffee (Coffea spp.), tea (Camellia sinensis), and mate (Hex 
paraguayensis); (c) cocaine from Erythroxylum coca; (d) coniine from hemlock (Conium 
maculatum); (e) and nicotine from tobacco (Nicotiana tabacum). 



toxic, the highest amounts being found in the roots and leaves. The alkaloids 
are readily absorbed through mucous membranes. 



Vll. METHYLXANTHINES 

The most widely consumed alkaloids worldwide are, without a doubt, the 
methylxanthines. Of these, caffeine (Fig. 6) is far and away the leader. 
Worldwide caffeine consumption has been estimated to be 70 mg/day/person, or 
some 1.1 x 10 8 kg per annum (120,000 tons) (Spiller, 1984; Max, 1986). Caffeine 
is contained in tea, coffee, cocoa, chocolate, headache remedies, and soft drinks. 
Although caffeine is found in at least 63 plant species, most of the world's 
consumption derives from two Coffea species and the tea plant, Camellia 
sinensis. Of the world's consumption of caffeine, coffee accounts for 54% and tea 
for 43% (Max, 1986). The caffeine in soft drinks is derived from the process of 
decaffeinating coffee, a pharmacological illustration of the principle that what 
you lose on the swings you gain on the roundabouts. The average daily intake 
for U.S. adults is 2.5 mg/kg/day, and for Europeans, 3.5 mg/kg/day (Stavric, 



275 



254 Huxtable 

1988a). The motivation for this enormous consumption is, of course, the central 
nervous system stimulation people get from caffeine Theobromine, the major 
xanthine in chocolate, only has weak central actions, due to its low liposolu- 
bility (Stavric, 1988b). Caffeine is addictive, the withdrawal syndrome involv- 
ing headaches and lassitude. Apart from this, the methylxanthines have low 
toxicity in adults, numerous studies failing to sustain a relationship between 
caffeine consumption and risk of cardiovascular disease (e.g., Grobbee et al., 
1990). 

The form in which caffeine is consumed varies from country to country. Tea 
consumption ranges from 3.44 kg/yr/capita in Ireland to 0.02 kg/yr/capita in 
Thailand Coffee consumption is highest in Finland at 12.41 kg/yr/capita. In 
the United States, it is 4.68 kg'yr/capita. These numbers apply to 1981-1982 
(Max, 1986). This represents a 54% drop since 1960, the difference being made 
up by the consumption of caffeine-containing soft drinks. In 1982, Americans 
drank 149 L/yr/person of such beverages. 

Caffeine consumption is clearly within the pharmacological range. The 
minimum stimulant dose in humans falls between 85 and 250 mg. Average per 
capita daily consumption in the United Kingdom is around 165 mg, in the 
United States around 246 mg, and in Finland 465 mg. A considerable fraction 
of the populations of these countries, of course, consume much greater 
amounts. Thus, while the daily mean intake for the United States has been 
calculated as 2.6 mg/kg, the upper decile was 7.0 mg/kg (Dews, 1984). There is 
no doubt, therefore, that caffeine is the world's most widely consumed 
behaviorally active alkaloid. It is, in the words of one investigator, a model drug 
of abuse (Holtzman, 1990). 

Although this massive consumption of alkaloids seems relatively innocuous, 
mankind perhaps receiving more benefit than harm from "the reviving brew" or 
a fragrant cup of coffee, it may pose a developmental hazard. A noted 
researcher in pharmacokinetics once told me that she had never performed a 
plasma analysis on a baby that did not show the presence of caffeine. Even 
pregnant or nursing women who eschew coffee may be exposed to caffeine from 
a variety of other sources. Babies are exposed to caffeine both in utero and via 
the milk. Although the average mean intake may be low — for the United States 
estimated to be 0. 18 mg/kg for babies under the age of 1 year (Dews, 1984) — the 
16-20 times longer half-life of excretion, discussed above, due to the lack of 
liver metabolizing enzymes means that even a low daily intake of caffeine can 
lead to an accumulating body burden (Aldridge et al., 1979; Aranda et al., 
1979). The developmental consequences of caffeine exposure is a generally 
unconsidered aspect of the wide use of this generally safe substance. Although 
developmental studies in humans are difficult (it is next to impossible to find a 
control group of unexposed babies, for one), the results of animal experiments 
give cause for alarm. Known developmental effects based on animal studies 
include increased circulating catecholamine levels in the fetus, decreased 
placental weight, lactate accumulation, and altered uterine perfusion. When 
nursing rats were given caffeine equivalent to a human consumption of 
approximately three cups of coffee a day (rats metabolize caffeine faster), 
protein concentration in the brains of the pups was significantly increased, 



276 



Toxicology of Alkaloids 



255 



while the levels of zinc and activities of zinc-dependent enzymes such as 
alkaline phosphatase decreased (Nakamoto et al., 1989). When caffeine 
exposure was combined with the additional stress of protein malnutrition, a 
different spectrum of changes obtained. 

VIII. ERGOT ALKALOIDS 

Perhaps the best-known examples of alkaloidal contamination of food come 
from the epidemics of ergotism that ravaged Europe at intervals throughout 
the Middle Ages. Ergot is a fungus, Claviceps purpurea, which grows on the 
ears of rye, Secale cereale. Ergot alkaloids are mevalonylindole Gysergic acid) 
derivatives, major ones being ergotamine and ergonovine (Fig. 7). These com- 
pounds have a complex pharmacology. A major action is the a-adrenergic 
agonism which causes profound and long-lasting constriction of vascular beds. 
If exposure continues long enough, gangrene results. 

Ergotism has existed for as long a rye has been used as cereal. Out- 
breaks are recorded on Assyrian clay tablets from 600 B.C. (Tanner, 1987). 
The consumption of moldy bread produced the medieval epidemics known as 



HOCH,CHNHOC 
I 
CH 3 



^X 





H CH2C5H5 



(b) 



Figure 7 (a) Ergonovine and (b) ergotamine alkaloids of ergot (Claviceps purpurea). 



277 



256 Huxtable 

St. Anthony's fire. It has been claimed that events as disparate as the Salem 
witch trials in New England and the lack of increase in the European popula- 
tion during the Middle Ages were consequences of the consumption of rye bread 
containing the products of the unwanted mold (Matossian, 1989). With the shift 
in consumption to wheat bread and better regulation of food con taminat ion, 
ergotism slowly ceased to be a major public health problem. Outbreaks, how- 
ever, still occur, as a result of improper storage or processing of rye. If rye is 
stored damp, ideal conditions obtain for the growth of these parasitic molds. In 
this century, major outbreaks occurred in Russia in 1926, in Ireland in 1929, 
and in France in 1953. In Africa, an outbreak was recorded in 1979 in Ethiopia. 
Iatrogenic ergotism is not uncommon. Alkaloids such as ergotamine are 
used clinically in the treatment of migraine, and cases of intoxication from such 
usage are known (e.g., Macguire and Cassidy, 1990). Ergot alkaloids are potent 
oxytocins, certain of them, such as ergonovine, having been used therapeutic- 
ally to induce labor. However, oxytocin itself is replacing ergonovine in current 
practice. 

DC OTHER ALKALOIDS 

In a short chapter, it is impossible to review all the alkaloids to which humans 
are exposed by means of foods and herbs. The chewing of Catha edulis Forsk., 
or khat, is common in parts of Africa for the mild stimulation afford by 
cathinone, an alkaloid with amphetaminelike actions. The khat habit is now 
spreading in Europe. In the summer of 1990, 1 observed a man selling khat in 
the railway station in Amsterdam. Sanguinaria alkaloids are added to tooth- 
pastes, cough remedies, and mouthwashes in the United States and are used in 
other parts of the world as folk remedies. The use ofNicotiana leaves as tobacco 
is legion, and as consumption in the United States falls, so it rises in other 
parts of the world. Poisoning has occurred in the United States from the use of 
nicotine-containing chewing gum, and death has resulted from the consump- 
tion of the leaves of N. glauca, a common, naturalized plant in many parts of 
America (Castorena and Garriott, 1987). The quality of life for many people is 
also markedly affected by their dietary levels of histamine and tyramine. 

X. PRINCIPLES FOR INVESTIGATION OF HERBAL POISONINGS 

A recent case of pyrrolizidine poisoning in Switzerland has engendered discus- 
sion out of proportion to its intrinsic significance because some basic rules of 
investigation were not observed. It involves the diagnosis of hepatic veno- 
occlusive disease in a 5-day-old female, who died 33 days later (Roulet et al., 
1988). Exposure to pyrrolizidines had occurred in utero from the mother's 
persistent consumption of herbal tea. According to the manufacturer, the tea in 
question contained 10 plant species, including 9% of Tussilago farfara, or 
coltsfoot The authors believed this without confirniing it by their own botani- 
cal analysis. Thin-layer chromatography indicated a senecionine content in the 
tea of 0.6 mg/kg dry weighL However, T. farfara contains not senecionine but 
the alkaloid senkirkine (Fig. 5) (Sommer, 1989). Others have concluded that 



278 



Toxicology of Alkaloids 257 

the plant involved was a Petasites species, probably P. hybridus, because it 
grows in the area the mother lived (Anonymous, 1988). However, actual 
analysis of a tea sample by another laboratory showed the presence of the two 
pyrrouzidine-containing species, T. farfara and P. officinalis (Spang, 1989). 

A number of general conclusions can be drawn from this one case. First, if 
possible, an actual sample of the herb consumed should be obtained. Regard- 
less of labeling or of information from the manufacturer, botanical analysis 
should be done if possible on the sample and on other, separately purchased, 
samples of the same product. Botanical identification alone, while important, is 
insufficient due to the wide variability in alkaloid content from sample to 
sample. Chemical analysis should be done to establish (1) that pyrrolidines 
are present, (2) which alkaloids are present, and (3) in what concentration they 
are present. Estimates can be obtained as to the quantity of material con- 
sumed, the period of time over which it was consumed, and the extraction 
efficiency of the alkaloids under the conditions of preparation employed. This 
allows mg/kg body weight exposures to be calculated, as has been done in the 
case of the Arizona poisonings and other intoxications (Stillman et al., 1977; 
Huxtable, 1980a; Ridker et al., 1985). In the Swiss case, however, no indica- 
tion was given as to how the analysis was performed, and no dose calculations 
were done. 

These, of course, are councils of perfection. Often, the material is in such a 
state of division or decomposition that botanical analysis is difficult (see the 
photographs in Huxtable, 1989a). Analytical facilities may not be available. 
But without these steps, it will be impossible to gauge either the true incidence 
of pyrrolizidine poisoning or the threshold levels of consumption posing risk 
(Huxtable and Awang, 1990). 

Rational standards for herbs and food supplements would include (1) proper 
botanical identification of the plants used; (2) assays of chemical content of 
active ingredients, and standards for what these levels should be; (3) controls 
for purity, including botanical, microbiological and chemical contamination 
and filth levels for insect parts, animal hairs, and rat feces; and (4) appropriate 
storage and handling conditions. 

XI. ACKNOWLEDGMENT 

My own work over the years on pyrrolizidine alkaloids and herbal intoxications 
has been supported by USPHS grant HL-25258. 

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284 



Comments on the Risks of Pyrrolizidine Poisoning from Comfrey (Symphytum) 

Given the widespread use of comfrey-containing products and the small number of documented 
cases of poisoning associated with such use, it is perhaps understandable that the public is reluctant to 
accept the toxicity of such preparations. However, the toxic agents in comfrey are pyrrolizidine 
alkaloids. Many plants contain pyrrolizidines, and if pyrrolizidine alkaloid poisoning is viewed as a 
whole, the risks of comfrey can be seen in context Pyrrolizidines occur in more than 60 genera of 
plants, including the important Crotalaria, Senecio, Symphytum and Hetiotropium. Pyrrolizidines from 
different plant species vary in chemical structure and in the amount needed for toxicity. The major 
toxic effect is liver damage; specifically veno-occlusive disease. Certain pyrrolizidines also cause 
cancers, lung disease, or affect other organ systems, such as the brain, gastrointestinal tract or kidneys. 

Numerous cases of pyrrolizidine poisoning are known, including epidemics in the Caribbean, 
South Africa and central Asia as a result of the use of plants as herbs or food, or because plants have 
contaminated food grains. Human poisoning by pyrrolizidine alkaloids has been recently reviewed 
(Huxtable, 1989). Furthermore, there is an excellent World Health Organization publication on risks 
to humans (United Nations Environment Programme and International Labour Organization, 1988). In 
addition to the documented cases of plant poisoning, there have been frequent reports of veno- 
occlusive disease of the liver from unknown causes. Veno-occlusive disease is a highly specific 
condition, caused only by certain anti-cancer agents or pyrrolizidine alkaloids. These numerous reports 
of veno-occlusive disease of unidentified cause dating back at least a century from all over the world 
can be presumed to represent pyrrolizidine poisoning. In the older literature, veno-occlusive disease is 
known as endophlebitis hepatica obliterans. 

It can be concluded, therefore, that reports of pyrrolizidine poisoning, implied or explicit, are not 
uncommoa Why are there not more reported cases of comfrey poisoning? There are a number of 
reasons for this, including: the delayed nature of poisoning, symptoms perhaps not appearing until 
months or years following exposure; the cumulative nature of pyrrolizidine poisoning, whereby 
symptoms develop in response to a total dose of alkaloids regardless of the period over which it was 
taken; and the nonspecific chronic nature of pyrrolizidine poisoning. Veno-occlusive disease is an 
early response which may not become clinically apparent. Over a period of time this leads to cirrhosis 
of the liver, which if diagnosed may be ascribed to other causes, including alcohol. Perhaps most 
important, however, is that pyrrolizidine poisoning from the use of comfrey has not been systematical- 
ly looked for. Cause -effect relationships are rarely obvious, but have to be carefully sought. By way 
of illustration, tobacco was smoked for centuries before an association with lung cancer was suspected. 
It then took thirty years of intensive research to establish the association, yet even now some still 
dispute it. Susceptibility to poisoning can also be expected to vary from individual to individual, for a 
number of reasons, including the use of other drugs, gender, age, state of health and cultural habits. 
For example, certain anticonvulsants increase the toxicity of pyrrolizidine alkaloids. Among one group 
of Indians poisoned by the herbal use of Hetiotropium , two who died were taking phenobarbital for 
epilepsy (Mattocks. 1986). 

Where pyrrolizidine poisoning is suspected, investigation is often not carried out properly. The 
literature is full of confusing reports, as Dr. Awang indicates, because proper botanical identification 
was not done, proper chemical analysis performed, or dose calculations made (Huxtable and Awang, 
1990). Where dose levels have been calculated, some interesting results are found (Table 1). On the 
table, the doses resulting in toxicity in humans have been normalized in terms of rat LD^ units. This 
is the amount of pyrrolizidine needed to kill half of the rats in a test group. This table suggests that 
humans are much more sensitive to pyrrolizidine poisoning than are rats. The table also suggests that, 
expressed in this way, threshold levels producing toxicity in humans are remarkably consistent from 
plant to plant and alkaloid to alkaloid. The high levels seen with, for example, the S. longilobus 
poisonings are probably a reflection of supratoxic doses being administered to babies over a compara- 
tively short time. 



285 



In conclusion, there is every indication that the consumption of Symphytum is a health risk. The 
risk varies depending on the part of the plant consumed, the age of the plant, the type of preparation, 
the pattern and frequency of the use, and certain characteristics of the user. There is no corresponding 
benefit to offset the risk. Symphytum is banned in Germany (Tyler, 1987), and echimidine-containing 
Symphytum species and varieties are banned in Canada. Although the United States prides itself on 
the regulatory mechanisms protecting the public health, Symphytum is still freely sold in this country. 

References 

Huxtable. RJ. 1989. pp. 41-86 In Toxicants of Plant Origin, Vol I: Alkaloids. PJR. Cheeke (ed) Boca 

Raton. FL: CRC Press. 
Huxtable. RJ. and D.V.C. Awang. 1990. Pyrrolidine poisoning. AmJMed. 89: 547-548. 
Mattocks, A.R. 1986. Chemistry and Toxicology of Pyrrolidine Alkaloids. London: Academic Press. 
Tyler, V.E. 1987. Plant drugs in the twenty-first century. HerbalGram #11: 6-11. 
United Nations Environment Programme, , International Labour Organization and World Health 

Organization 1988. Environmental Health Criteria 80: Pyrrolidine Alkaloids. Geneva: World 

Health Organization 



286 



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Drug Safely 5 (Suppl. !l: 126-136. 1990 
01 14-5916/90/0001 -01 26/J5. 50/0 
<S ADIS Pros Limned 
All rights reserved. 

OSSUP1 783 



The Harmful Potential of Herbal and Other 
Plant Products 

Ryan J. Huxtable 

Department of Pharmacology, College of Medicine, University of Arizona, Tucson. 
Arizona, USA 



Summary 



Herbs, herbal products, food additives and other dietary supplements derived from 
plants are widely consumed in many countries. The literature on intoxications from such 
behaviour is increasing. This article reviews some of the factors predisposing to intoxi- 
cation from the use of herbs, with examples drawn largely from pyrrolidine alkaloid- 
containing plants. 

Poisonings occur because of the misidentification of a plant, or the unknown or ig- 
nored toxicity of a correctly identified plant. Factors contributing to problems include 
the difficulties of identifying chopped, processed herbs or plant mixtures, persistent use 
of a toxic plant, variability in the toxic constituents of a plant, problems of nomenclature, 
adulteration and the difficulty in establishing the chronic toxic potential of a plant. 

Certain users of herbs are at high risk of intoxication. These include chronic users, 
those consuming large amounts or a great variety, the very young, fetuses, the elderly, 
the sick, the maJnounshed or undernourished and those on long term medication. Mem- 
bers of certain cultural groups in North America are also at higher nsk. Certain plant 
toxins may be gender-selective in their action. 

To encourage discussion, some approaches to regulation are suggested, and some com- 
monsense guidelines are given. 



There are estimated to be around 500,000 flow- 
ering plant species, or angiosperms, in the world. 
This is a highly successful group, having evolved 
in the presence of grazing and browsing animals, 
insect pests, parasites and bacteria. As plants are 
usually immobile, for defence they rely on physical 
structures, such as thoms and spines, and chemical 
means. The chemical defences of flowering plants 
are extremely sophisticated, and it is not surprising 
that many plants are toxic to humans. Plant chem- 
icals are still the backbone of our pharmacopoeia. 
In the United States, 25% of prescriptions written 
are for plant products, and another 25% are for 



agents based on plant products. The chemical con- 
stituents of herbs should thus be viewed as one 
would view any manufactured drug or chemical in 
assessing health nsk or safety. 

In the following discussion, many of the ex- 
amples are drawn from pyrrolizidine-contatning 
herbs. Apart from my personal interest in this group 
of alkaloids, these are emphasised because of their 
widespread geographical and botanical distribution 
(more than 300 species of pyrrolizidine- 
containing plants in more than 60 genera in at least 
13 families), the chronic and cumulative nature of 
pyrrolizidine toxicity, and the frequent use of 



288 



Harmful Potential of Plants and Herbs 



127 



pyrrolizidine-coniaining plants as herbs and diet- 
ary supplements. 

I. Causes of Herbal Poisoning 

1.1 Mistdentification of Plant Species 

Poisonings can occur when a misidentified toxic 
plant is consumed instead of an intended safe plant. 

Misidentification can occur in commercially sold 
plants. A women in Missouri suffered atropine poi- 
soning after drinking a tea prepared from deadly 
nightshade (Airopa belladonna), sold by one of the 
largest herb companies in America, in mistake for 
comfrey {Symphytum species) [Anon. 1983; Croom 
E, personal communication]. A similar case has 
been reported from England (Galizia 1983). A death 
was reported in England of a person drinking 
mate, sold as Ilex paraguayensis. but which, 
judging from the clinical picture, was probably a 
pyrrolizidine-containing species (McGee et al. 
1976). In the western United States. 2 species of 
Compositae, Senecio longilobus and Gnaphalium 
macoumi have been commercially sold under the 
same herbal name, gordolobo. The Senecio species 
is toxic, and has been responsible for a number of 
deaths and illnesses Fox et al. 1978; Huxtable 1 980; 
Stillman et al. 1977). Gnaphalium is apparently 
non-toxic. Some have considered that the 2 plants 
may have been confused, because of their similar 
phenotype. 

Misidentification can also occur in self-collect- 
ed, or non-commercially collected plants. A couple 
in the state of Washington died after preparing a 
tea from foxglove (Digitalis) in mistake for com- 
frey (Cooper et al. 1977). A similar case has been 
reported from England (Bain 1985). Other cases of 
self-collected Digitalis poisoning are known (Dick- 
stein & Kunkel 1980). A team on a desert survival 
course in southern California became ill, with 1 
member dying, after a salad was prepared from a 
Datura species (jimson weed) mistaken for a harm- 
less species (Huxtable 1980). 

1.2 Unknown or Ignored Toxicity of a 
Correctly Identified Plant 

Toxicity studies have been earned out on only 
a few of the large number of flowering plant species 
in the world. For many common plants there is a 



lack of information concerning their chemical con- 
stituents or their long term toxic potential. It ap- 
pears that humans are much more sensitive to pyr- 
rolidines than are laboratory animals such as rats. 
Human deaths have been reported after exposure 
to a fraction of a rat LD50 (Huxtable 1989a; United 
Nations Environment Programme 1988). Even 
where the toxic potential of a plant has been es- 
tablished, it may be ignored by commercial sup- 
pliers or private collectors. Comfrey species have 
long been known to contain hepatotoxic and po- 
tentially carcinogenic pyrrolidine alkaloids (Cul- 
venor et al. 1980a; Hirono et al. 1978, 1979; Svo- 
boda & Reddy 1972). However, the plants are 
widely consumed in the form of herbal tea, a veg- 
etable, tablets and capsules in many countries. Sev- 
eral cases of comfrey poisoning have been de- 
scribed (Bach et al. 1989; Huxtable 1989b; Ridker 
et al. 1985; Weston et al. 1987) and other unpub- 
lished cases are known (Huxtable 1989b; Beckham 
N, personal communication). 

2. Factors Contributing to Potential 
Problems with Herbs 

2. 1 Difficulties of Identification 

Commercial products may contain plant parts 
that have been chopped, that lack flower parts or 
other identifying structures or are otherwise al- 
tered. Figure 1 shows a sample of tea responsible 
for the death of a woman in southern Arizona. The 
tea was sold under the name 'te mar' and the 
woman drank a gallon a day for 3 days before laps- 
ing into a coma and dying. Despite the physical 
state of the tea, a tentative identification of a Cro- 
ton species was made based on the presence of stel- 
late hairs (Huxtable 1989b). Figure 2 shows 3 sam- 
ples of gordolobo. obtained from 3 locations in the 
American southwest. One of them is a sample ob- 
tained from the parents of a 9-week-old boy who 
died after drinking a lea prepared from it (Fox et 
al. 1978). This was identified as Senecio longilobus. 
The other 2 samples were identified as Gnaphal- 
ium macounu. Figure 3 shows an example of a herb 
sold under the name "matanque'. A long term user 
of this preparation wished to know what it was. 



289 



128 



Drug Safeiv 5 (Suppl. 1) 1990 




Rg. 1. Difficulties of idenuficauon: an American woman died 
after drinking a large quantity of lea prepared from this herb. 
sold commercially in Mexico. 







— : — • . • --^'A'n^aB 




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Fig. 2. Of ihese 3 samples ol herbal lea. the upper left and 
the bottom were identified as Gnaphattum macounu. The 
upper right was identified as Senccio longtlohus and was re- 
sponsible for the death of a 9-week-old child. All 3 teas were 
sold commercially under the name gordolobo iStillman et al. 
1 977). 

These unidentifiable roots are likely lo be either 
Cacalia decomposua (a pyrroltzidine-containina 
species) or Psacatuim (Linares & Bye 1 987). 

2.2 Herbs Implicated in Poisoning Cases Ma> 
be Mixtures 

Four patients in Hong Kong developed hepato- 
megaly after taking a herb for psoriasis, and one 
died (Kumana et al. 1 983). The herb consisted of 



Fig. 3. These roots were sold under the name 'maianque' 
as a kidney prophylactic. Are they from the pyrrolizidine- 
conlaining Cacalia or the pyrrolizidine-free Psacaliuin? 
(Linares & Bye 1 987). 

64% by weight of leaves. 13% acorns, 10% dates. 
6% seeds, and 6% sticks. The seeds germinated into 
plants readily identified as Heliotropium lasiocar- 
pum, confirming these incidents as cases of pyr- 
rolidine poisoning (Culvenor et al. 1986). 

2.3 Lack of Demonstration of Safety and 
Efficacy of the Herb 

Ethical drugs in the United States have to com- 
ply with strict standards of safety and efficacy. Such 
standards are lacking for herbal preprations. Prep- 
arations may be widely used for years with no 
knowledge of their long term health risk. Thus, 
preparations of Borboma (Aspalaihus) are widely 
sold in North America, South Africa and elsewhere 
as caffeine-free teas, although no toxicity studies 
have been reported on them (Huxtable 1983; Watt 
& Breyer-Brandwijk 1962). Laetnle-containing 
preparations are widely used as cancer treatments, 
despite their lack of efficacy (Engelhardt & Caplan 
1989; Markle & Petersen 1980). 

2.4 Persistent Use of a Plant Known to be 
Toxic 

Although the toxicity of a plant may have been 
demonstrated, its herbal use may persist. Examples 
include Symphytum spp. comfrey (Huxtable 1989b) 



290 



Harmful Potential of Plants and Herbs 



i:9 



and Petaskes japonicus, another pyrrolizidine-con- 
taining species, which is used as a vegetable (Hi- 
rono et al. 1973). A 47-year-old woman who drank 
up to 10 cups of comfrey tea per day and also took 
comfrey pills, over a period of 1 year (fig. 4), de- 
veloped ascites and liver disease (Bach et al. 1989). 
A 13-year-old boy had been "treated' for Crohn's 
disease with comfrey root and comfrey leaf tea and 
was subsequently admitted to hospital with ascites 
and hepatomegaly (Weston et al. 1987). A 49-year- 
old woman took comfrey-pepsin capsules daily for 
6 months and was then admitted to hospital with 
portal hypertension and veno-occlusive disease 
(Ridker et al. 1985). An elderly woman who was 
admitted to hospital with veno-occlusive disease, 
portal hypertension and cirrhosis was a long term 
consumer of numerous herbs, taking several dozen 
preparations on a regular basis. For at least the 6 
months before admission, she had taken 6 com- 
frey-pepsin capsules per day (Huxtable 1989b). An- 
alysis of the latest batch she had been taking re- 
vealed a pyrrolizidine content of 988 mg/kg. 

An extract of Senecio cineraria was listed in the 
American Physicians Desk Reference until 1986 as 
an eyewash. Two cases of veno-occlusive disease 
have been reported from Switzerland after the 




Fig. 4. A range of comfrey-conlaining capsules and tablets 
sold as digestive aids. This is a selection obtained from a 
single health food store In view of the high and variable 
contents of pyrrolizidine alkaloids in some of these prepar- 
ations, 1 brand name is uncomfortably accurate (Huxtable 
et al. 1986). 



ingestion of Senecio teas (Margalith et al. 1985). 
Numerous herbal usages of other pyrrolizidine- 
containing species have been reported (Huxtable 
1989b). 

2.5 Variability in Chemical Constituents of 
Herbs 

Wide variations can occur in the levels of toxic 
constituents in herbs and may markedly affect the 
health risk posed by their use. The following fac- 
tors affect this variability: 

• The time of year or developmental stage at which 
the plant is collected. The fruit of the ackee plant 
(Blighia sapida) is harmless when npe, but toxic 
when unripe because of the presence of hypogly- 
cins, which block glucose synthesis in the liver 
(Bressler et al. 1969). The pyrrolizidine alkaloid 
content of Senecio leaves vanes widely from plant 
to plant, from month to month and from year to 
year (fig. 5) [Johnson et al. 1985). Older Symphy- 
tum leaves have lower levels of alkaloids than the 
younger leaves (Culvenor et al. 1980b). 

• The part of a plant used to prepare the herb. 
Symphytum roots have a higher level of alkaloids 
than the aerial pans (Roitman 1981). The pyrrol- 
izidine content of comfrey-pepsin capsules has been 
found to vary from 270 mg/kg 10 2900 mg/kg, de- 
pending on whether leaves or roots were used in 
the preparation (Huxtable et al. 1986). 

• The area in which the plant is collected. Senecio 
longilobus from Gardner Canyon, Arizona, has been 
found to contain up to 18% pyrrolizidine alkaloids 
by dry weight, the highest level recorded for any 
plant (fig. 5) [Johnson et al. 1985]. 

• Conditions of storage and length of time the herb 
is stored. The toxicity of Crotalana decreases with 
storage because of breakdown of pyrrolizidines 
(Heath et al. 1975). 

2.6 Problems with Nomenclature 

Major sources of confusion occur with the nu- 
merous botanical binomials that may have been 
applied to a plant, the large number of common 
names that may be used, and the lack of corre- 



130 



291 



Drug Safeiv 5 (Suppl I) 1990 



20 

I 1S 
a 

■ 
On 

5 

4 
>. 
Q 5- 




May Jun Jul Aug Sep Oct 





Mullein Nicotians 


VerOascum 
lhapsus 


y/^ Punchon / 
Tobacco Cimarron 


\s^ Canoelana 




Verbasco 



Gordolobo Senecio longiloOus 

Gnapnahum macounii — Manzanilla 
^^-^^ del Hio 

G. wnghtii — ^"^ 

Fig. 6. Inter-relauonships between herbal names and scien- 
tific binomials for the gordolobo complex in the southwest 
United Stales and northern Mexico. 



100 



5 7.5 
o 



5.0 



i • 

«r 2.5-I 



0.0 




Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov 



Fig. 5. The time and place: variation in pyrrolizidine alka- 
loid content of Senecio leaves, (a) S. rtddellii collected from 
Woodward. Oklahoma. The curves show the mean of 4 to 5 
consecutive years' collections, with the maximum year-to- 
year ranges, (b) S. longibbus collected from Gardner Can- 
yon, Arizona. The curves show the mean of I to 4 years' 
collections, with maximum year-to-year ranges. The data have 
been recalculated and curves redrawn from Johnson et al. 
(1 985). 



spondence between the 2 systems. Even within the 
same language, the common name of a given spe- 
cies may vary from area to area, and the same 
common name may be applied to 2 or more 
species. 

Chamomile in Europe may be German cha- 
momile, Matricaria recutita, or Roman chamom- 
ile, Chamaemelum nobile, formerly Anthemis no- 
bilis. In the western United States, Anthemis cotula 
is sold as chamomile. In the American southwest 
and in Mexico, chamomile is usually called man- 



zanilla. In Mexico, however, it is typically Matri- 
caria which is sold as manzanilla. Common Eng- 
lish names for Anthemis cotula include dogs' 
chamomile, stinking mayweed and dog fennel. An 
example of the lack of correspondence between 
common names and scientific binomials is the 
Verbascu m/gordoiobo complex in the American 
southwest (fig. 6). At least 3 species have been 
identified as having been sold under the herbal 
name gordolobo. One of these species is Verbas- 
cum thapsus. But Verbascum thapsus is also sold 
herbally under a variety of other names, some of 
which are shown in figure 6. 

A further example of numerous synonyms from 
a circumscribed area is the names by which Cim- 
icifuga racemosa is known in the Carolinas. these 
include black snakeroot. black cohosh, cohosh, false 
cohosh, squaw root, papoose root, blueberry, yel- 
low ginseng, blue ginseng, columbine-leaved leon- 
tice, meadow-rue leontice, richweed. battle weed, 
rattle-root, bugbane, rattlesnake root, heart-leaved 
rattle top, rattle top, cordate rattle top and heart- 
leaved snakeroot (Croom 1983). To complicate 
matters, in the same area, in addition to C. race- 
mosa. Asarum canadense. Samcula canadensis and 
5. manlandica are also known as black snakeroot. 

For the middle American region, Morton lists 
31 common synonyms for Heliotropium angio- 
spermum, 21 for H. curassavicum and 38 for H. 
indicum, with considerable overlap between them 
(Morton 1981). Extracts of all these plants are con- 
sumed ethnomedically, and the last 2 species con- 
tain toxic pyn-olizidines (Mattocks 1986). 



292 



Harmful Potential of Plants and Herbs 



131 



The problem is confounded in the literature be- 
cause in many cases authors do not establish the 
identity of the plants they are concerned with by 
proper botanical analysis. The practice of 'trans- 
lating' herbal names into scientific names in the 
absence of proper identification is to be deplored, 
as it gives a spurious accuracy to the results. An 
example is the case of a woman in Missouri who 
developed veno-occlusive disease after drinking 2 
litres per day, for 6 weeks, of a herbal tea pur- 
chased in Ecuador (Lyford et al. 1976). On the ba- 
sis of the herbal names, it was assumed that one 
of the plants she consumed was Crotalana juncea. 
In fact, although the diagnosis of veno-occlusive 
disease implies pyrrolidine poisoning, the plant 
source must be considered unestablished. 

2.7 Difficulty in Establishing the Long Term 
Toxic Potential of a Plant 

Plants which are acutely toxic cause problems 
when they are consumed in ignorance or by acci- 
dent, problems which by their nature are localised. 
With plants having long term or cumulative ef- 
fects, the problems include the following: 

• The length of time between exposure to the cause 
and the production of an effect. 

• The nonspecific nature of the effects, such as 
cirrhosis or cancers occurring from exposure to 
pyrrolizidines. 

• The lack of a mechanism for collecting obser- 
vations and other data on which firm conclusions 
may be drawn. If an association is not looked for. 
it is not likely to be found. Despite hundreds of 
years of use by millions of people, the carcinogenic 
action of tobacco smoke was only established in 
the past 2 decades after extensive research. 

• Difficulties of dose calculation. Even where her- 
bal poisoning is suspected, dose calculations are 
often difficult. It may be impossible to get a sample 
of the actual herb consumed (Heath et al. 1975), 
or a sample taken at one point in time may not 
accurately reflect the average exposure over a pe- 
riod of time. Thus, in an Indian outbreak of veno- 
occlusive disease, poor correlation was found in the 
affected villages between the pyrrolizidine content 



of grain in the households, and the presence of 
veno-occlusive disease in the households (Knsh- 
namachan et al. 1977; Siddiqi et al. 1978; Tandon 
et al. 1976a, b). In other words, the sampling of 
grain was not truly representative of what the 
families had been eating. 

2.8 Adulteration 

Herbal products can be adulterated, intention- 
ally or otherwise. Amborum Special F is a herbal 
remedy claimed to contain no western medicine 
and no cortisone. Two patients in Switzerland took 
this Californian-obtained herb for the treatment of 
asthma and rheumatism. One patient developed 
Cushing's syndrome and the other adrenal Cortisol 
suppression. The herb was found to be adulterated 
with betamethasone (Knoblauch et al. 1989). 

Tyler (1987) quotes surveys of ginseng products 
in which 60% of marketed items contain little or 
no ginseng. 

A related problem was found with a supposedly 
'decocainised' tea prepared from Erythroxvlum 
leaves which is widely consumed in the United 
States. Analysis revealed levels of cocaine com- 
mensurate with those in untreated leaves (Siegel et 
al. 1986). 

3. Herbal Users in Groups at Higher Risk 
of Toxic Consequences 

3. 1 Long Term Users 

The longer the period over which a herbal prep- 
aration is consumed, the greater the likelihood of 
delayed or cumulative toxic consequences. Veno- 
occlusive disease developed in a woman taking 
comfrey-pepsin capsules with each meal over a pe- 
riod of months (Ridker et al. 1985). The other re- 
ported cases of Symphytum poisoning also involve 
long term users. 

3.2 Consumers of Large Amounts 

Toxicity typically occurs in people consuming 
amounts which, by any standards, must be consid- 
ered unreasonably high, as in the previously men- 



293 



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Drug Safely 5 (Suppl. I) 1990 



tioned case of the woman who died after drinking 
one gallon of 'te mar' tea a day for several days 
(Humble 1989a). Another example is that of a 
child who suffered water intoxication from the large 
volume of herbal tea her parents fed her (Lipsitz 
1984). 

3.3 Users of a Wide Variety of Herbs 

The greater the number of herbal products con- 
sumed, the greater the chance that one of them may 
be toxic, and the greater the possibility of inter- 
actions between them. A young woman suffered 
excessive menstrual bleeding and depressed clot- 
ting factors after putting herself on a regimen of 
40 herbs, plus aspirin, dextropropoxyphene, para- 
cetamol, carisoprodol, various vitamins and bro- 
melain. She had persisted in this regimen for a 
number of years. For the two months before seek- 
ing medical attention, she had drunk large quan- 
tities of a tea prepared from tonka beans, melilot 
and woodruff, all plants containing coumanns. In 
all, she was consuming 9 substances that interfered 
with her blood coagulation (Hogan 1983). The 
patient referred to earlier who developed veno-oc- 
clusive disease after taking comfrey-pepsin cap- 
sules was also taking daily supplements of ascorbic 
acid, vitamin K, tocopherol and B complex, leci- 
thin, stereotropic adrenobovine extract, salts of 
calcium, magnesium, potassium, zinc and iron, 
chamomile tea plus other herbal teas. After her 
condition had been treated surgically, she was sub- 
sequently readmitted with encephalopathy after the 
consumption of 200g of protein in a 1 2-hour pe- 
riod (Ridker et al. 1985). 

3.4 Babies 

Babies are at special risk because they may typ- 
ically be dosed with herbs at a higher level per kg 
bodyweight than adults would consume, and be- 
cause babies lack the hepatic drug biotransforma- 
tion and detoxification enzymes. If the mother is 
imbibing herbs, babies may also be exposed to plant 
chemicals via the milk Nursing rats fed Senecio 
can excrete pyrrolidine alkaloids in the milk in 



doses harmful to their sucklings (Schoental 1959). 
Veno-occlusive disease has been reported in South 
African babies when no pyrrolidine alkaloids 
could be found in the herbs they had been given 
(Stein & Isaacson 1962). It is possible that they may 
have been exposed via their mother's milk. A num- 
ber of cases of young children poisoned with teas 
prepared from Seneao longilobus have been re- 
ported from Arizona (Fox et al. 1978; Huxtable 
1980; Stillman et al. 1977). 

3.5 Fetuses 

Many plant chemicals freely cross the placental 
barrier. Equivalent blood concentrations in mother 
and child may be harmless to the one and toxic to 
the other, as shown by the fetotoxicity of com- 
monly consumed substances such as alcohol, to- 
bacco, caffeine and phenytoin. A case has recently 
been reported from Switzerland of a baby poisoned 
in utero by herbal tea the mother had consumed; 
the baby died within a few weeks of birth (Roulet 
et al. 1988). 

3.6 The Elderly 

The pharmacological responses of elderly peo- 
ple can differ markedly from those of the young 
(Montamat et al. 1989). The elderly account for 
10% of the population but consume 25% of pre- 
scribed drugs (Kayne 1978). In addition, there may 
be decreased attention paid to the amount of herbs 
consumed, other health problems may be present, 
and there is increased intake of over-the-counter 
medications. Certain chronic conditions, such as 
cirrhosis, may be exacerbated by herbal constitu- 
ents or may lead to altered pharmacokinetics of 
such constituents. 

3.7 The Sick 

Illness can lead to increased susceptibility to 
toxins, because of increased mobilisation of fat 
stores and the chemicals deposited in them. In ad- 
dition, the increased intake of prescription and 
over-the-counter drugs allows increased opportun- 



294 



Harmful Potential of Plants and Herbs 



133 



ities for unfavourable interactions. Another kind of 
adverse effect is produced when a person uses herbs 
to treat a medical condition which could benefit 
from conventional therapy. The widespread use of 
laetnle as a supposed treatment for cancer is a 
pnme example (Engelhardt & Caplan 1989; Markle 
& Petersen 1980). 

3.8 The Malnourished or Undernourished 

Malnounshment or undernourishment in- 
creases the risk of an unfavourable response to 
herbs. The outbreaks of veno-occlusive disease and 
hypoglycaemia that occurred in the West Indies in 
the 1950s because of the consumption of bush teas 
prepared from Senecio and Crotatana and from the 
unripe fruit of Blighia sapida were exacerbated by 
the poor nutntional status of the exposed popu- 
lation. In one typical case, a 10-month-old male 
admitted with veno-occlusive disease had been fed 
only on Quaker Oais plus diluted condensed milk, 
with breast milk at night. The Quaker Oats 
amounted to 225g per week shared with 2 other 
children. Two weeks before admission with veno- 
occlusive disease, he had been severely poisoned 
by castor oil seeds (Rianus communis) [Hill et al. 
1951]. This case illustrates the way in which a 
number of nsk factors can come together. 

3.9 Gender 

Plant chemicals may have toxic effects which 
are gender-dependent. Pyrrolizidine toxicity is a 
consequence of metabolism, and males are more 
effective metabolisers than females (fig. 7). 




100 200 300 400 500 

Monocrotalme perfused (»imol/L) 




100 200 300 400 

Monocrotalme perfused (ymol/L) 

Fig. 7. Effect of gender and phenobarbital preireatment on 
pyrrolizidine metabolism in ihe isolated liver. Hepatic me- 
tabolism of pyrrolizidines such as monocrotalme is a pre- 
requisite for toxicity Male rats exnibit a higher rate of me- 
tabolism than do female rats, and metabolism in both genders 
is accelerated by prior exposure to phenobarbital. (•) Rats 
received phenobarbital (100 mg/kg intrapentoneally) and then 
were maintained on 0. 1% phenobarbital in drinking water for 
3 days, and received up water I day prior to use; (O) un- 
treated animals (Lafranconi &. Huxtable 1984). 



3.10 Those on Long Term Medication 



The use of herbs by individuals receiving long 
term medication with ethical drugs poses the nsk 
of herb-drug interactions, and exposes the individ- 
ual to the consequences of hepatic induction of 
metabolising enzymes. Five individuals were poi- 
soned by pyrrolizidine-containing herbal teas in In- 
dia. The 2 who died were taking phenobarbital as 
an anticonvulsant. Phenobarbital is known to in- 



duce the lethal biotransformation of pyrrolizidines 
(fig. 7) [Datta et al. 1978]. In the previously dis- 
cussed case (section 3.3) of the patient with de- 
pressed clotting factors, the woman's condition was 
produced by interactions between over-the-counter 
medication and constituents of the herbs she was 
consuming (Hogan 1983). 



295 



134 



Dnig Safetv 5 (Suppl. 1) 1990 



3.1 1 Cultural Groups 

Certain cultural groups in North America are 
heavy consumers of herbs and may rely on health 
and medical care obtained outside the 'official' 
health care system (Curtin 1974; Felger & Moser 
1974, 1985; Ford 1975; Martinez 1978: Moerman 
1977; Spicer 1981). Such groups include certain 
Mexican-American and other Laun-Amencan 
groups, Amenndians, and certain immigrant 
groups, such as those originating in south-eastern 
and eastern Asia. Various pyrrolizidine-containing 
plants have been reported to have ethnopharma- 
cological and ethnobotanical uses in a number of 
these groups (reviewed in Huxtable 1989b). A 
striking example of high risk ethnomedicine was 
the use of pure lead oxides to treat 'empacho' in 
Mexican-American children (Ackerman et aJ. 1982; 
Baer et al. 1987). It has been documented that lead 
oxides, sold under the names 'azarcon' and 'greta', 
have been fed to children in California, Texas, Col- 
orado and other western states (Max 1984), and 
there is every indication that these powders are 
widely used in Mexico. Although not a plant prod- 
uct, the use of 'azarcon', an orange powder, may 
derive by analogy from the use of azafran to treat 
'empacho'. Azafran is an orange powder prepared 
from the false saffron. Canhamus tinaorius. 

4. Regulatory Suggestions 

In terms of risk-benefit analysis, if the nsk is 
small but the benefit zero, the nsk must be con- 
sidered unacceptable. However, people clearly de- 
rive psychological benefits from their herb-taking 
behaviour and this must be considered in a nsk- 
benefit analysis. 

Possibilities to be considered include the 
following: 

I) The development of a list of plants consid- 
ered safe for consumption in quantity. Such plants 
could be used without restriction in herbal prod- 
ucts. Italy is an example of a country implementing 
this approach. 2) The development of a list of 
plants which are acute or chronic toxins and which 
should be banned from herbal products, e.g. Con- 



turn. Zygadenus. Symphytum. 3) The develop- 
ment of a list of plants of which certain parts are 
considered too toxic for use. 4) The development 
of a list of plants which present a finite but 'ac- 
ceptable' risk, which may be used in small (de- 
fined) quantities in herbal products. 5) A require- 
ment that labelling provide accurate, acceptable 
botanical identification, with a statement as to the 
known or unknown toxicities. 6) A requirement 
that herb manufacturers with a certain (defined) 
volume of business employ a qualified botanist. 
7) A requirement for products to carry warning la- 
bels, e.g. 'This product is not approved by the FDA 
for the treatment or prevention of any medical 
condition.' 8) A demand for toxicity testing of sel- 
ected plants along the lines of a manufactured drug. 
9) A demand for education directed towards mak- 
ing consumers more aware of the risks of 'natural' 
materials. 10) The production of a more scientifi- 
cally literate society (Hellerstein 1989). 

Some commonsense guidelines for the public are 
as follows: 

• if ill. see a doctor 

• do not take herbs if pregnant or attempting to 
become pregnant 

• do not take herbs if you are nursing 

• do not give herbs to your baby 

• do not take a large quantity of any one prep- 
aration 

• do not take any herb on a daily basis 

• buy only preparations on which the plants are 
listed on the packet (no guarantee of safety or 
correctness, but better than nothing) 

• do not take anything containing comfrey. 

Acknowledgement 

Work from the author's laboratory was supported by 
USPHS N1H HL 25258. 

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AZ 85724. USA. 



298 



Chapter 4 



Neurotoxins in Herbs 
and Food Plants 

Ryan J. Huxtable 



1. INTRODUCTION 

The modern flora has evolved in the face of continual assault from mammals, which are 
ultimately dependent on the plant kingdom. In addition to the physical defenses of spine, 
barb, thorn, and other devices, plants have developed complex systems of chemical 
defenses, varying enormously from genus to genus and family to family. The chemicals 
used, however, are classifiable under a relatively small number of structural headings, 
such as acetogenins, sugars, and modified amino acids. Most common plant secondary 
metabolites, including alkaloids, glycosides, steroids, and terpenes, can be subsumed 
under these headings. These substances deter because of their taste or because of their 
noxious or fatal effects on animals consuming them. 

Plant predators, in turn, have evolved systems of defenses against plant chemicals. 
However, plants and those using them coexist in an uneasy balance of chemical power. In 
evolution, absolute tactical success is absolute strategic failure. If herbivores became too 
efficient in combating the chemical defenses of plants, numerous species in both king- 
doms would become extinct. Conversely, if plants suppressed predation, the extinction of 
the animal kingdom would be rapidly followed by the impoverishment of the plant 
kingdom, as successful species colonized space and other resources. 

Man protects himself from plant toxicity by relying on a relatively small number 
of highly selected cultivars for the bulk of his nutritional needs. Cultivars are plant 
varieties not occurring naturally, but derived culturally by selective breeding. These 
include corn (Zea spp.), wheat (Triticum spp.), rice (Oryza sativa), barley (Hordeum 
spp.), potatoes (Solanum spp.), and beans (Phaseolus spp.). Even so, many cultivars are 

Rvan J. Huxtable • Department of Pharmacology. College of Medicine. University of Arizona. Tucson. 
Arizona 85724. 

The Vulnerable Brain and Environmental Risks. Volume I : Malnutrition and Hazard Assessment, edited by 

Robert L. Isaacson and Karl F. Jensen. Plenum Press. New York. 1992. 

77 



299 



78 Ryan J. Huxtable 

or can be highly toxic, and have to be stored or prepared with certain precautions. Thus, 
cassava (Manihot esculenta), used by millions of people in the tropical and subtropical 
worlds, must undergo a lengthy preparation to remove the cyanogenic glycoside, 
linamarin. Beans have to be aggressively boiled to inactivate their phytohemagglutinins 
(lectins) (Liener, 1983), and potatoes and tomatoes have to be harvested and stored 
appropriately to keep the levels of steroidal alkaloids in the safe range (Dalvi and Bowie. 
1983; Jadhav et al., 1981; Sharma and Salunkhe, 1989). Lectins, in fact, are present in 
numerous food plants, including fruits, spices, nuts, and cereals. Rye, although no longer 
extensively used, was for centuries a mainstay for the underclasses of Europe. A parasitic 
infestation of rye was responsible for the massive outbreaks of St. Anthony's fire, or 
ergotism, which alternated with the plague in punctuating the population growth of the 
continent. 

Paradoxically, other plants are consumed in vast amounts because of their effects on 
the central nervous system. Such plants include coffee (Coffea spp.), tea (Camellia sinen- 
sis), marijuana (Cannabis spp.), mate (Ilex paraguayensis), and cocoa (Theobroma 
cacao). Such human use has spread vast plantations of these plants in areas remote from 
their native ranges and has ensured that, whatever else of Nature's botanical cornucopia 
may vanish forever in man's heedless pillage of natural resources, these species will 
survive for as long as the farmer. Thus, in a roundabout way, the defensive chemicals 
evolved by these plants are successful in ensuring the survival of their biosynthesizers. 

The history of plants is the history of medicine. Plant products affecting the nervous 
system are legion, and little more than a brief overview can be attempted here to discuss 
the types of compounds involved and to refer the reader to more specialized literature. In 
the main, discussion has been limited to ethnobotanically significant compounds; that is to 
say, neurotoxins from plants used as foods or plants used ethnopharmacologically. Even 
here, constraints of space necessitate picking through the topics like a jaded party-goer 
faced with another bowl of nuts. 



2. MAMMALIAN DEFENSES AGAINST PLANT TOXINS 

Xenobiotics are non-nutritive chemicals found but not formed in the body. They are 
frequently toxic. The first line of defense against ingested xenobiotics is to prevent or 
reduce absorption. The high acidity of the stomach, transport-limited processes of absorp- 
tion, and breakdown by gut microflora all serve in their limited ways to filter out dietary 
toxins. 

Following absorption of a potentially toxic xenobiotic. mammals typically rely on an 
integrated triad of processes for defense: oxidation, conjugation, and excretion. Hepatic 
oxidation occurs via enzymes such as the cytochrome P 450 mixed-function oxidases. 
These are inducible enzymes, their activity rising on chronic or subacute exposure to a 
substrate. Oxidation increases water solubility of the substrate. Solubility is increased 
further by conjugation with such endogenous substances as glutathione, sulfate, or 
glucuronate. The oxidized and conjugated xenobiotic is released into the bloodstream, to 
be excreted via the kidneys into the urine. Usually, on oxidation both the degree of binding 
to plasma proteins and the biological half-life of the xenobiotic are sharply decreased. 
Thus, caffeine is almost totally metabolized in adults (Cornish and Christman, 1957) but 
almost unmetabolized in premature babies. As a result, while the half-life of caffeine is 



300 



Neurotoxins in Herbs and Food Plants 79 

4.9 ± 1.8 hr in adults, in premature babies it is 102.9 ± 17.9 hr (Aldridge etal., 1979; 
Dews, 1984). 

Most at risk for the expression of toxicity are the gastrointestinal tract and the liver, 
because these organs are exposed to the highest concentrations of xenobiotics. In conse- 
quence, these organs have developed specialized protective mechanisms. Both organs 
have high regenerative capacity, and the liver has mechanisms for enzymatic detoxifica- 
tion. Next at risk is the kidney, which tends to accumulate metabolized and unmetabolized 
xenobiotics for urinary excretion. In certain cases, hepatic conjugates can be further 
metabolized and bioactivated in the kidney, producing toxicity (Dekant et al. 1989; Koob 
and Dekant, 1991). The lung is another organ at risk, as substances released from the liver 
come into intimate contact in a relatively concentrated form with the capillary bed of the 
lung. Thus, in laboratory rodents, hepatic metabolites of the pyrrolizidine alkaloid, mono- 
crotaline, produce pulmonary arterial hypertension (Huxtable, 1990a). 

Despite its lack of regenerative capacity, in the main the central nervous system is 
well protected from xenobiotics. The increase in water solubility following hepatic oxida- 
tion militates against entry into the brain. For lipid-soluble substances, other compart- 
ments in the body compete with the brain. Substances with affinity for protein bind to 
plasma albumin. Additionally, the blood-brain barrier provides a further defense against 
the entry of xenobiotics. In all, a primary neurotoxic action is uncommon for plant 
xenobiotics, although substances can cause hepatic encephalopathy due to a derangement 
of nitrogen metabolism in the liver. 

The Maginot line of the gastrointestinal tract can be bypassed, invalidating the 
hepatic defenses behind it. Certain substances, such as coniine, cocaine, nicotine, or 
tropane alkaloids such as scopolamine or atropine, are absorbed across mucous mem- 
branes, such as the vagina, nose, or mouth, while numerous others are absorbable by the 
lungs when inhaled as dust or smoke. This is often the preferred method of administration 
for centrally active substances, such as cocaine or nicotine, precisely because they avoid 
the first pass through the liver, ensuring that greater amounts rapidly reach the brain. 
Hamlet's father was fraternally murdered by means of a plant extract being poured into his 
ear as he slept. The plant has been tentatively identified as Conium maculatum, a source 
of coniine (Max, 1988a). 

Despite their relative scarcity, plants with actions on the central nervous system have 
been avidly sought by many cultures. Such plants include those elaborating caffeine and 
the related methylxanthines; morphine; reserpine; the ungrammatically named psyche- 
delics and hallucinogens, such as mescaline, tetrahydrocannabinol, lysergic acid, and 
psilocybin; and the terpenes present in absinthe and spices. 



3. PLANT NEUROTOXINS 

Neurotoxic plant chemicals can be classified in a number of ways. These include 
their pharmacological action (e.g., excitant, depressant, psychotomimetic, narcotic), their 
mechanism of action, the receptor systems they act on (e.g., muscarinergic, nicotinergic, 
dopaminergic, serotonergic, glutaminergic), or their botanical source. In this chapter, 
plant neurotoxins will be grouped according to their chemical structures. Three main 
groups of compounds will be considered — alkaloids, amino acids, and monoterpenoids — 
along with a fourth, miscellaneous group. 



301 



80 



Ryan J. Huxtable 



H 3 CO 



H 3 CO 




OCH3 



OCH, 




Emetine 



R - OH Lysergic acid 

R - N(CH 2 CH 3 ) 2 Lysergic acid diethylamide (LSD) 

R - NHCH(CH 3 )CH 2 OH Ergonovlne 



HO. 



\^K^>- ~NCH 3 
HO^\^ 






Morphine 




N(CHj) 2 




R - H Dlmethyltryptamlne 

R - OH Psllocln 

R - OPOjHj Psilocybin 



Cathlne 



H3CO 




8300 Y^Y""^ 




OCH3 

Harmine Mescaline Cathlnone 

FIGURE 1. Neurotoxic alkaloids: Nonterpenoid alkaloids derived from aromatic amino acids. 



Plant alkaloids are related, biogenetically and structurally, to mammalian neurotrans- 
mitters. With a few exceptions, they are basic derivatives of amino acids, typically formed 
by decarboxylation, which may be combined with other metabolic fragments. Thus, 
simple decarboxylation plus minor modifications yields mescaline (Fig. 1) from tyrosine, 
psilocybin and psilocin (Fig. 1) from tryptophan, and histamine from histidine. Combina- 
tion of decarboxylated and deaminated aromatic amino acid fragments yields morphine 
(Figs. 1 and 5) or benzylisoquinoline alkaloids, such as papaverine. Other metabolic 
fragments include an acetate-derived mevalonate in the case of ergot alkaloids, such as 
ergonovine (Fig. 1), or a mevalonate-derived monoterpenoid C 9 or C, fragment in the 
case of the complex indole alkaloids, such as reserpine or strychnine (Fig. 2). Exceptions 



302 



Neurotoxins in Herbs and Food Plants 



81 



H 3 CO 




OCH, 



OCH, 



Reserpine 



OCH, 





O CH 3 



O N' 
I 
CH 3 



Strychnine Ibogamlne 

FIGURE 2. Neurotoxic monoterpenoid and purine alkaloids. 



Caffeine 



to this definition of an alkaloid include colchicine, which, although derived from tyrosine 
and phenylalanine, is a nonbasic N-acetyl compound, and the xanthines, caffeine (Fig. 2), 
theobromine, and theophylline, which are methylated derivatives of purine. 

Almost without exception, alkaloids have pharmacological actions, largely due to the 
ability of the amine function to interact by charge transfer, proton transfer, hydrogen 
bonding, or ion bonding with numerous sites in the body. Actions on the central nervous 
system depend on the liposolubility of the alkaloid. This, in turn, is a function of the 
basicity. The greater the basicity of the alkaloid, the greater the proportion that is ionized 
at physiological pH and the lower the partition coefficient into lipid compartments such as 
the brain. Liposolubility also depends on the ratio of hydrophilic to hydrophobic groups 
on the molecule. Thus, phenolic groupings are more hydrophilic than the corresponding 
methyl ethers, while large aryl and alkyl substituents increase liposolubility. 

Apart from their marked pharmacological effects, alkaloids tend to be bitter tasting. 
Foods containing them tend to be aversive. Exceptions include the monoamines, such as 
tyramine and serotonin, present in many foods, such as bananas, cheese, beer, choc- 
olate, and fish, and contributing to the characteristic taste of these substances. Alkaloid- 
containing materials are, however, frequently taken as herbs or for their psychoactive 
effects. 

Amino acids tend to be much more hydrophilic than alkaloids, partly because of their 
dipolar nature, and partly because of their lower molecular weights. In general, they 
contribute little to the taste or smell of the foods containing them. However, some, such as 
glycine and arginine, have distinctive tastes, while acidic amino acids tend to be flavor 



303 



82 Ryan J. Huxtable 

enhancers, accentuating the taste of foods in which they are present. Although plants 
contain many unusual amino acids that are non-nutritive to mammals, in the main these 
substances have little neurotoxicity. This is partly because concentrations are low in plants 
and partly because entry into the brain is limited by poor liposolubility. Important excep- 
tions include the neuroexcitatory plant amino acids. These occur in certain plants, such as 
Lathyrus, Sativa, or Cvcas, which are or were widely consumed, are neurotoxic in low 
concentrations, and enter the brain either in the circumventricular regions where blood 
vessels contain a fenestrated endothelium (i.e., the blood-brain barrier is not patent), or 
possibly by utilizing active transport systems for physiologically important amino acids. 

The third group of neurotoxins to be considered is the monoterpenes. Terpenes derive 
from acetate via the intermediacy of mevalonate and isopentenyl pyrophosphate. Com- 
pounds such as tetrahydrocannabinol, one of the principal active components of mari- 
juana, can be considered to be a modified monoterpene plus an olivetol fragment. Mono- 
terpenes are responsible for the fragrance and taste of many pungent plants, such as the 
mints (Mentha spp.). They are highly liposoluble. If the liver fails to oxidize them 
sufficiently, they pass readily into the brain. They tend to be pharmacologically active, as 
the potency of their odors might indicate, and their smell derives from high-affinity 
activation of a chemoreceptor. Indeed, a qualitative relationship between olfaction or taste 
and central nervous system action is suggested by the culinary use of plants containing 
capsaicin (Capsicum spp.), the myrosinolates in the mustards (Cruciferae) and capers 
(Capparidaceae) (Kjaer, 1976, 1978), and sulfur compounds, such as those adding pi- 
quancy to materials ranging from coffee to mushrooms (Huxtable, 1986). 

Overall, the importance of plant neurotoxins in the development of neurophar- 
macology cannot be overstated. The kainate and quisqualate subtypes of excitatory amino 
acid receptors and the muscarinic and nicotinic cholinergic receptors are all named for the 
plant chemicals that led to their discovery. Quisqualate is found in the seeds of the Chinese 
plant, Quisqualis chinesis (or Q. indica), while kainate comes from the red alga, Digenia 
simplex (Takemoto, 1978). 



3.1. Neurotoxic Alkaloids 

The major neurotoxic alkaloids encountered in foodstuffs and herbs are listed in 
Table 1 . There has been a marked and continuing increase in the number of alkaloid- 
containing plants sold as teas, herbs, herbal remedies, food additives, and food supple- 
ments in North America. Of the 200 species Siegel (1976) reported as being sold as 
smoking mixtures and the 400 species being sold as teas or food supplements, many are 
alkaloidal. The species included Corynanthe yohimbe (yohimbine). Cola spp. (methyl- 
xanthines). Lobelia inflata (lobeline), Argemone mexicana (berberine), Nicotiana spp. 
(nicotine), Ilex paraguayensis (caffeine), Ephedra spp. ( pseudoephedrine or ephedrine, 
depending on whether the plant derives from the New World or Old), Passiflora incarnata 
(harmine alkaloids), Catharanthus roseus (indoles), Rauwolfia serpentina (reserpine), and 
Datura spp. (tropane alkaloids). At least in the United States, these substances are largely 
unregulated. Not being sold as food or drugs, but as food additives, food supplements, or 
herbal remedies, they escape regulation by the Food and Drug Administration. 

The class of plant compounds generating the most intense lay and professional 
interest is that known variously as hypnotics, psychotomimetics, psychedelics, psycho- 



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306 



Neurotoxins in Herbs and Food Plants 85 

dysleptics, hallucinogens, or pyschotropics (Emboden, 1979). This clutter of ill-defined 
terminology perhaps expresses the confusion of conflicting feelings such compounds 
generate. Do plants such as Mandragora officinarum or Datura represent "the insane root 
that takes the reason prisoner," as Banquo would have it, or do they provide a release from 
the cage of the body, with its imprisonment in space and time (Huxley, 1970)? But even 
Shakespeare is ambivalent, another of his characters concluding that, "We are such stuff 
as dreams are made on," and that life is merely an insubstantial pageant. The temptation 
to use these compounds to explore reality beyond the limits of the self has proven to be an 
irresistible allure to many (Dobkin de Rios, 1984; Emboden, 1979; Schultes and 
Hofmann, 1980). People of all cultures and times have taken advantage of the chemical 
ingenuity of plants to escape, temporarily, the travails of a fleshly existence. 

Mind-altering or mind-expanding drugs variously alter self-consciousness, the sense 
of time and space, and the perception of the physical world. How such a definition varies 
from that of sleep is problematic. The relationship between consciousness (the state), the 
mind (the perceiving entity), and neurochemical alterations in the brain is opaque. One 
should not think that the discovery that hallucinogens or morphine bind to certain recep- 
tors in the brain and affect certain neurochemical processes somehow "explains" the 
effects of these chemicals on perception. 

In most settings, "expanding the mind" impairs function. One function of con- 
sciousness is to triage or filter out the overwhelming and confusing mass of sensory input 
assailing us by the second. Writing an article takes a narrowed, focused consciousness. So 
does avoiding a predator or finding food. "Expanding the mind" safely can only occur in 
a structured, protected setting. It is not to be wondered at that most societies have drawn 
strict social or religious rules around the use of agents that alter perception. 

3.1.1. Convulsants, Hallucinogens, and Psychotomimetics 

Among the worst of toxins and the best of pharmacological agents is that plethora of 
peptide and nonpeptide tryptophan derivatives known as the ergot alkaloids. These are 
produced by a parasitic fungus, ergot (Claviceps purpurea), growing on rye (Secale 
cereale). The resultant contamination of the rye bread on which the peasantry of Europe 
subsisted for so many centuries was responsible for the terrible disease of ergotism, or St. 
Anthony's fire (Barger, 1931; Matossian, 1989; Schultes and Hofmann, 1980). Just one 
outbreak of ergotism in France in 994 AD killed 40,000 (Schultes and Hofmann, 1980). 
Ergot was never the problem in England it was on the continent, as rural workers in 
England never subsisted exclusively on rye (Barger, 1931). 

Ergotism takes both a peripheral and a central form. The more common peripheral 
form involves alkaloid-induced vasoconstriction, leading to scintillating pain in the ex- 
tremities, gangrene, and loss of limbs. The central form involves delirium, convulsions, 
and hallucinations. 

The peripheral form, ergotism gangrenosus, is caused by the peptide alkaloids in 
ergot, while the central form, ergotism convulsivus, is caused by the nonpeptide lysergic 
acid amides. The natural variation in the ratio of these two classes of alkaloids is the 
probable reason for the variation in the clinical expression of ergotism. The forms were 
also differentiated geographically, presumably for the same reason, with the convulsive 
type being common east of the Rhine and the gangrenous type west of the Rhine. 

Better public health measures and an increased liking for bread made from wheat 



307 



86 Ryan J. Huxtable 

rather than rye have attenuated the incidence of ergotism in the 20th century. Although 
largely a disease of the past, ergotism is not unknown in modem Europe. Major outbreaks 
occurred in Russia in 1926. in Ireland in 1929. and in France in 1953. In the Russian 
outbreak, over 1 1.000 people were affected in an area stretching from Kazan. 400 miles 
east of Moscow, to the Ural Mountains. Numerous deaths were reported (Barger, 1931). 
Outside of Europe, an outbreak occurred in 1979 in Ethiopia. 

On the credit side, ergot has proven a veritable potpourri of valuable pharmacolog- 
ical agents (Goodman and Gilman et al., 1990). Over two dozen alkaloids have been 
isolated. In the central nervous system, ergotamine acts as an a-adrenergic antagonist, 
while ergonovine and methylergonovine act as partial agonists or antagonist at seroton- 
ergic and dopaminergic receptors. These compounds are esters of lysergic acid (Fig. 1). 
Centrally acting alkaloids affect the vasomotor center, giving rise to the vasodilator, 
hypotensive, and bradycardiac effects of ergot. The psychotomimesis appears to be due to 
the hypothalamic actions. 

Among the numerous hallucinogenic plants used by the Aztecs of Mesoamerica was 
one the seeds of which they named ololiuqui. For years the botanical identity of this plant 
was shrouded. In a 16th-century Aztec drawing made for the Spanish physician, Francisco 
Hernandez, ololiuqui resembled an Ipomea, or morning glory, species, but no halluci- 
nogen had been found in a morning glory. By the dawn of the 20th century, the consensus 
was that ololiuqui was probably Datura meteloides, although in the Aztec drawings 
ololiuqui did not look solanaceous, and the effects of taking ololiuqui were not those to be 
expected for atropine, the psychoactive agent in Datura. The true ololiuqui was re- 
discovered for western science in 1939, growing in a Zapotec Indian garden in the 
Mexican state of Oaxaca (Schultes and Hofmann, 1980). Hidden from criticism, the use 
of the plant had survived the overthrow of the Aztec empire by 400 years, and had 
survived the successor Spanish empire. The plant was a morning glory, Rivea corymbosa. 

The hallucinogens in Rivea are lysergic acid amides, similar to those present in ergot. 
It is a strange happenstance of biochemistry that species so botanically and geographically 
separated should make the same complex alkaloids. In both species, biogenesis involves 
the linking of an isoprene unit with tryptophan. 

The chemist. A. Hofmann, discovered the hallucinogenic properties of lysergic acid 
diethylamide serendipitously, while purifying it (Swain, 1975). This compound is particu- 
larly effective as a serotonin antagonist. What on the one continent had been considered a 
visitation of the devil was on another seen as a visitation of the gods. 

Another Mesoamerican species, Ipomea violacea, has been spread around the world 
as an ornamental. The seeds of the plant, also used by the Zapotecs as a hallucinogen, 
contain five times the level of lysergic acid amides as does R. corymbosa. The sight of 
Ipomea growing wild on the ruins of the Aztec temples at Teotihuacan instills a sense of 
carpe diem — the ruler and the ruled, all gone; in the words of the Elizabethan dramatist, 
James Shirley: 

Sceptre and crown 

Must tumble down. 

And in the dust be equal made 

With the poor crooked scythe and spade 

Following the chemical analysis of these Mesoamerican plants, their use or abuse 
became popular among segments of the American population in the 1960s. Numerous 
cultivars were developed, with evocative names such as Heavenly Blue. Pearly Gates, and 



308 



Neurotoxins in Herbs and Food Plants 87 

Wedding Bells. In the 1990s, however, their use seems to have been largely replaced by 
the various cultivars of light beer. 

Although all cultures had access to hallucinogens, the Aztecs were the most single- 
minded in their institutional pursuit of the visionary world revealed by such agents. The 
use of alcohol, however, was strictly banned, except for the old. A partial listing of 
Nahuatl words (the language of the Aztecs) for hallucinogenic plants shows the following: 
coanenepilli (Passiflora jorullensis; 3-carboline-type alkaloids, such as harmine); 
cochiztzapotl {Casimiroa edulis: N-benzoyltyramine and other psychoactive compounds); 
pipiltzintzintli (Salvia divinorum); coazhuitl (Rivea corymbosa); tlitliltzin (Ipomea vio- 
tacea), and toloache (Datura spp.). Three of the plants used by the Aztecs were consid- 
ered so potent that they were elevated to godhood: the above-discussed ololiuqui; peyott 
(the dried heads of the cactus Lophophora williamsii or L. diffusa, containing the halluci- 
nogenic mescaline or simple tetrahydroisoquinolines such as pellotine); and teonanacatl 
(the word literally meaning "'flesh of the God" — a Psilocybe mushroom containing 
psilocybin or 4-phospho-N,N-dimethyltryptamine). Psilocybin is dephosphorylated to 
yield the actual hallucinogen, psilocin (Fig. 1). 

Hallucinogenic mushrooms have been revered in many cultures (and feared in as 
many others). Wasson has developed a theory of mycolatry, or mushroom worship, based 
on the pharmacological activities of the Mesoamerican Psilocybe and the old world 
Amanita species (Wasson, 1979, 1980). The obvious phallic symbolism of mushrooms is 
made explicit in much an of both the New and Old World. 

The psychotropic mushroom, Amanita muscaria. has been equated with the soma of 
the old Ayurvedic scripts (Wasson, 1968). Soma conferred immortality on those consum- 
ing it. The active agent in A. muscaria is the GABA-mimetic, muscimole (Fig. 3) (Tyler. 
1963). Muscimole is an artifact of isolation, being formed from ibotenic acid (Fig. 3). 
Others dispute the identification of A. muscaria as soma. Indeed, one could stock a fair- 
sized garden with species proposed as candidates over the years. Current front-runners 
"include Ephedra sinica, source of ephedrine (McCaleb, 1990), and Peganum harmala, 
source of harmaline (Flattery and Schwartz, 1989; Jones, 1990). In modern times, Aldous 
Huxley reintroduced soma into his Brave New World, but there it tasted of strawberry ice 
cream, and those taking it toasted their own annihilation rather than immortalization. 

The use of peyotl in a religious setting survives in the Native American Church and 
elsewhere (Anderson, 1980; Myerhoff, 1974). Mescal buttons, or the dried heads of the 
plants, are chewed. This is not to be confused with Agave, or an alcoholic drink made 
from Agave, both of which are also known as mescal. Mescaline is present in a number of 
other cacti, including the South American species, San Pedro, Trichocereus pachanoi, 
which is also an object of hallucinogenic use. 

Other hallucinogenic plants used by various cultures include Bamsteriopsis, Lobelia. 
Tagetes. and Pegamum (Emboden, 1979; Schultes and Hofmann, 1979). Banisteriopsis 
caapi is used in South America under a variety of regional names, including caapi. 
ayahuasca. yaje, and caddna. It contains 3-carbolines. These substances act as mono- 
amine oxidase inhibitors, potentiating the actions of both endogenous monoamines, such 
as epinephrine and norepinephrine, and exogenous monoamines, such as N.N- 
dimethyltryptamine. In a nice example of ethnopharmacology, users of B. caapi often add 
tryptamine-containing plants to the preparation, thereby taking advantage of the potentiat- 
ing properties. 

Tropane alkaloids such as atropine have both anticholinergic actions on the auto- 
nomic nervous system and central psychotomimetic actions. An intoxicated individual is 



309 



H,C 




Domoic ackl 



HO 



Ryan J. Huxtable 



NH, 



'CHRNH, 



R--CC>2H Ibotenicadd 
R - H Muscimole 



NC-CH 2 CH-C02H 

P-Cyanoalanlne 



CO,H 

I 

CHNH, 

I 

CH 2 NHCH 3 



COjH 

I 

CHNH, 

I 

CH 2 NHCOC0 2 H 



OjNCHjCHjCOjH 



P-N-methylaminoalanine p-N-oxarylaminoalanine 3-Nitropropionate 

FIGURE 3. Muscimole and neurotoxic acids. 



described in mnemonic phrases as hot as a. hare, dry as a bone, blind as a bat. mad as a 
hatter, and red as a beet. Atropine itself is an artifact of isolation, being formed from the 
racemization of 1-hyoscyamine. 

The well-established ethnobotanic place of the these Datura, Atropa, and 
Hyoscyamus alkaloids is indicated by the species epithet for A. belladonna. The name, 
bella donna, or beautiful lady in Italian, stems from the cosmetic use of plant extracts to 
induce mydriasis, with the accompanying wide-eyed look considered so attractive in 
certain cultures. The obverse of the plant's pharmacological effects is given by the com- 
mon English name, deadly nightshade, and by the genus name. Atropa was one of the 
three fates, the daughters of necessity. While Clotho spun the thread of life and Lachesis 
allotted each man's portion, Atropos cut the thread at the appointed time, her name 
deriving from the Greek for "not turning." 

Datura poisoning is one of the more common plant intoxications in North America 
(e.g., Ulrich et al., 1982). These plants are consumed as a result of commercial con- 
tamination of other plants (Awang and Kindack, 1989), or misidentification or lack of 
knowledge of their toxicity by persons collecting for themselves. D. stramonium is sold as 
an asthma medication, and poisonings have occurred as a result (Feenaghty, 1982). Many 
poisonings result from the intentional use of Datura for its psychotomimetic effect. 
Typically it is taken as a tea. D. stramonium is also smoked as a hallucinogen. Occasion- 
ally, accidental poisonings occur, as with a group on a desert survival course in southern 
California (Huxtable, 1990b). A couple in Canada were poisoned following the accidental 
addition of Datura seeds to hamburgers (Anonymous, 1984). 

The convulsants, strychnine and brucine, come from the Indian tree, Strychnos 



310 



Neurotoxins in Herbs and Food Plants 



89 



nuxvomica. Strychnine blocks postsynaptic inhibition at glycinergic sites and is a valued 
tool in the study of amino acid neurotransmitter mechanisms. This highly complex al- 
kaloid was first isolated in 1817, but its structure was not elucidated until 1946. 

South American Strychnos, such as S. toxifera. are the source of the curare alkaloids, 
such as toxiferine I, used ethnobotanically as arrow poisons (the Greek word for which 
giving us our word, toxic) (Gardner and Sakiewicz, 1963). These are quaternary dimeric 
compounds that, unlike the tertiary alkaloids from S. nuxvomica, do not penetrate the 
central nervous system. Their major action is that of neuromuscular blockade at the 
nicotinic cholinergic receptor (Mclntyre, 1972). Curare is a resinous extract of various 
plants from the Orinoco and Amazon basins. Depending on preparation and storage, it is 
classed as calabash, pot, gourd, or tube curare, the latter being packed into bamboo tubes. 
At one time, the alkaloid composition of these classes varied, although in this century this 
seems to be no longer true. d-Tubocurarine, isolated from tube curare, derives from 
Chondrodendron tomentosum. Quaternary alkaloids are present in all types of curare, and 
pot and calabash curare additionally contained tertiary alkaloids. These lack effect at the 
neuromuscular junction, but are central convulsants. 

Yams {Dioscorea spp.) are solanaceous plants comprising a major food source in 
tropical countries. Worldwide production is about 20 million tons per annum (Jadhav ex 
al., 1981). In certain west African communities, yams may supply half the calories. Many 
wild species are highly toxic due to their content of isoquinuclidine alkaloids such as 
dioscorine (Fig. 4). This alkaloid, which has convulsant effects on the central nervous 
system, can be partially removed by soaking and leaching the yams in water. 




CH 2 OH 



OCOCHC 6 H 5 



OCOC 6 H 5 




H 3 C0 2 C 



I 
CH 3 

Atropine 




Cocaine 



s* 



N 



N 
CH 



J 



CH 2 OH 




Nicotine Lupinine 

FIGURE 4. Some neurotoxic pyridine and pipendine alkaloids. 



311 

90 Ryan J. Huxtable 

3.1.2. Stimulant or Euphoriant Alkaloids 

Worldwide caffeine consumption has been estimated to be 70 mg per person each 
day, or some 1.1 x 10° kg per annum (120,000 tons) (Spiller. 1984; Max, 1986). This 
makes caffeine the most widely consumed neuroactive substance in the world. It has been 
considered to be a model drug of abuse (Holtzman, 1990). Caffeine is contained in tea. 
coffee, cocoa, chocolate, headache remedies, soft drinks, and a variety of regional herbs 
and drinks. Although caffeine is found in at least 63 plant species, 54% of the world's 
consumption derives from two Coffea species, C. arabica and C. robusta. and 43% from 
the tea plant. Camellia sinensis (Max, 1986). The caffeine in soft drinks is derived from 
the decaffeination of coffee, a pharmacological illustration of the principle that what you 
lose on the swings you gain on the roundabouts. The average daily intake for U.S. adults 
is 2.5 mg per kg body weight, and for Europeans 3.5 mg (Stavric, 1988a). The motivation 
for this enormous consumption is, of course, the central nervous system stimulation 
people get from caffeine. Theobromine, the major xanthine in chocolate, has only weak 
central actions, due to its low liposolubility (Stavric, 1988b). Although other activities can 
be demonstrated in vitro, the central actions of caffeine result largely from its antagonism 
of purinergic receptors. 

Caffeine is addictive, the withdrawal syndrome involving headaches and lassitude. 
Apart from this, the methylxanthines have low toxicity in adults, numerous studies failing 
to sustain a relationship between caffeine consumption and the risk of cardiovascular 
disease (e.g., Grobbee et al., 1990). 

The form in which caffeine is consumed varies from country to country. Annual tea 
consumption ranges from 3.44 kg per person in Ireland to 0.02 kg per person in Thailand. 
Coffee consumption is highest in Finland, at 12.41 kg per person per year. In the United 
States, the corresponding figure is4.68 kg. These numbers apply to-498 1-1982 (Max, 
1986). This represents a 54% drop since 1960, the difference being made up by the 
consumption of caffeine-containing soft drinks. In 1982, Americans drank 149 liters per 
person of such beverages. 

Caffeine consumption is clearly within the pharmacological range. The minimum 
stimulant dose in humans falls between 85 and 250 mg. Average per capita daily con- 
sumption in the United Kingdom is around 165 mg, in the United States around 246 mg, 
and in Finland 465 mg. A considerable fraction of the populations of these countries, of 
course, consume much greater amounts. Thus, for the United States the upper decile is 
7.0 mg/kg, or three times the mean daily intake (Dews, 1984). 

Although this massive consumption of alkaloids seems relatively innocuous (Dalvi, 
1986), humankind perhaps receiving more benefit than harm from "the reviving brew" or 
a fragrant cup of coffee, it may pose a developmental hazard. It is difficult to find a 
newborn baby who does not have caffeine in the blood. Even pregnant or nursing women 
who eschew coffee may be exposed to caffeine from a variety of other sources. Babies are 
exposed to caffeine both in utero and via the milk. Although the mean intake may be low 
[for the United States it is estimated to be 0.18 mg/kg for babies under the age of one 
(Dews, 1984)], a 16-20x longer half-life of excretion, due to the lack of liver metaboliz- 
ing enzymes, means that even a low daily intake of caffeine can lead to an accumulating 
body burden (Aldridge et al.. 1979; Aranda et al.. 1979). 

The developmental consequences of caffeine exposure is a generally unconsidered 
aspect of the wide use of this generally safe substance. Although developmental studies in 
humans are difficult because of the near impossibility of finding a control group of 



312 



Neurotoxins in Herbs and Food Plants 91 

unexposed babies, the results of animal experiments give cause for alarm. Known devel- 
opmental effects based on animal studies include increased circulating catecholamine 
levels in the fetus, decreased placental weight, lactate accumulation, and altered uterine 
perfusion. When nursing rats were given caffeine equivalent to a human consumption of 
approximately 3 cups of coffee a day (rats metabolize caffeine faster), protein concentra- 
tion in the brains of their pups increased, while the levels of zinc and activities of zinc- 
dependent enzymes, such as alkaline phosphatase, decreased (Nakamoto et al.. 1989). 
When caffeine exposure was combined with the additional stress of protein malnutrition, a 
different spectrum of changes obtained, including increases in the levels of DNA and 
cholesterol in the brain. 

The first European to describe coffee drinking was Leonhard Rauwolf, for whom the 
genus Rauwolfia is named. In 1579, he observed the coffee habit in the Middle East. The 
drink quickly spread to Europe, spawning coffee shops, newspapers, and social inter- 
change. The introduction of tea came later, one of the first mentions in England being 
Samuel Pepys' diary for September 25, 1660. It was not long before Pope was already 
describing a young lady with nothing to occupy her time but to 

. . . spill her solitary tea. 

Or o'er cold coffee trifle with the spoon. 

The drinks have solaced many a European existence. The asthmatic novelist, An- 
thony Trollope, writes a few weeks before his death that, "Nothing seems to do me so 
much good as a cup of hot tea" (Trollope, 1983). Perhaps the most famous English tea 
drinker was Samuel Johnson, of whom Boswell muses, "I suppose no person ever en- 
joyed with more relish the infusion of that fragrant leaf." The artist. Sir Joshua Reynolds, 
alarmed on one occasion by the quantities Johnson was imbibing, reminded him that he 
had had 1 1 cups already. Johnson, annoyed, reprimanded him, "Sir, I do not count your 
glasses of wine. Why should you number my cups of tea?" and loudly called for a 
12th cup. 

A major plant of abuse in east Africa and certain Arab nations is khat, Catha edulis. 
Chewing the leaves and stems induces an amphetamine-like stimulation due to the pres- 
ence of a-aminopropiophenone, also known as cathinone (Fig. 1). Cathinone oxidizes 
readily in wilted plants to norpseudoephedrine (Fig. 1), which is much less active (Bren- 
neisen et al., 1986; Geisshiisler and Brenneisen, 1987). The appetite-suppressing effects 
of khat leads to a drug-induced anorexia in its users (Elmi. 1983). The khat habit is 
spreading to Europe with the immigration of formerly colonized peoples to the homelands 
of their colonizers. 

Like atropine, cocaine is a tropane alkaloid, although its pharmacology differs. This 
well-known agent, from yet another South American plant, Erythroxylon coca, functions 
peripherally as a local anesthetic and centrally as a stimulant or euphoriant. Its actions are 
subjectively indistinguishable from the amphetamines, although its mechanism is differ- 
ent. Whereas cocaine blocks the reuptake of neuronally released dopamine and other 
monoamines, the amphetamines increase the release of monoamines from intraneuronal 
storage sites. 

Given the entrepreneurial nature of American ingenuity, one can be assured that 
should supplies of South American cocaine be seriously interrupted, enterprising chemists 
will meet demand with the readily synthesized and almost infinitely variable amphet- 
amines. 

Cephaeline and emetine (Fig. 1) are emetic alkaloids from the Brazilian tree. 



313 



92 Ryan J. Huxtable 

Cephaelis ipecacuanha. This plant was used ethnomedicinally, and ipecac has passed into 
common usage around the world as an emetic in cases of poisoning. The action of the 
alkaloids is centrally mediated, involving stimulation of the chemoceptor trigger zone in 
the area postrema of the medulla (Manno and Manno, 1977). Vomiting occurs within a 
few minutes of ingestion. 

Motoneuron diseases precipitated by excitotoxic amino acids found in plants are 
discussed in Section 3.2. It has been reported that similar disease can be produced by 
ingestion of Lupinus seeds, probably L. albus (Agid et al., 1988). Such seeds are widely 
used for culinary purposes in Mediterranean countries, and their use is spreading to other 
countries. The toxicity of the quinolizine alkaloids such as lupinine (Fig. 4) in lupin has 
been well established. The toxicity of the seeds has been known since classical times. One 
method of preparation involves boiling to remove the bitterness (Sturtevant, 1919). In 
stock animals, excessive consumption of lupin leads to death from respiratory paralysis. 
Central nervous system involvement at lower levels of consumption is indicated by behav- 
ioral changes, including an affected animal standing with its head pressed against an 
object (Kingsbury, 1964). This is the first report, however, of primary neurotoxicity in a 
human associated with the consumption of lupin seeds (Agid et al., 1988). 

3.1.3. Narcotics and Tranquilizers 

Reserpine (Fig. 2), one of the first effective tranquilizers, comes from the Indian 
medicinal plant, Rauwolfia serpentina. Mahatma Gandhi supposedly used a tea made 
from the plant to help him in his periods of introspection and relaxation. Pharmacolog- 
ically, reserpine causes prolonged depletion of neuronal norepinephrine and serotonin 
stores. As the storage vesicles are destroyed, the effects of reserpine are long lasting, 
recovery of neuronal function being dependent on de novo synthesis of storage sites. 

The neurotoxic alkaloid that has wound the strangest and most revealing course 
through western history is doubtless morphine (Fig. 1). This compound is named for 
Morpheus, Ovid's name for the god of dreams, the name thereby revealing one of the 
most prominent subjective features of morphine intoxication. Morphine is isolated from 
the latex of the poppy, Papaver somniferum. The method of collecting the latex by 
incising the seed pod has remained unchanged for millennia. Opium is prepared from the 
dried latex. P. somniferum appears to be a cultivar of P. setigerum. although, like other 
species discussed in this chapter, it is a plant so domesticated, so cultivated, so selectively 
bred by man, that where it came from and what it came from are no longer easily 
discemable. No truly wild populations of P. somniferum are known. Individual plants can 
apparently be either diploid or polyploid, which again suggests that the "species" is a 
hybrid (Merlin, 1984). The modem pattern of distribution is related more to economics 
than to climate. Collecting opium is highly labor intensive, and so it is only produced in 
countries having a low cost of labor. Otherwise, the poppy grows happily, even in the 
environs of the northern city of Liverpool where the initial studies on its biosynthesis were 
carried out (Battersby et al.. 1964). 

The association of morphine and man is long standing, poppy seeds having been 
found in Neolithic sites in Europe dating to 5000 B.C. As the poppy is also the source of a 
valued oil. nutrition may possibly have been of more importance than the aspects of this 
varicolored flower that are so significant in modem times. However, the narcotic activity 
of opium was exploited early. The poppy is included in the prescriptions listed on a 



314 



Neurotoxins in Herbs and Food Plants 93 

Sumerian clay tablet in 2100 B.C. Opium was used by the Minoan, Ptolemaic, Assyrian, 
and Hellenic civilizations. Morphine has been detected in a Theban (Egyptian) funeral pot 
dating to about 1500 B.C. (Majno, 1977). Perhaps no substance has been more involved 
in man's search for a reality lying beyond reality, summarized in de Quincy's exultation, 
"Thou has the keys of paradise, O just, subtle and mighty opium" (de Quincey, 1948). 

Although morphine was isolated in crude form by the Parisian apothecary, Derosne, 
in 1803-1804, the credit for isolating crystalline morphine belongs to Sertiirner, who also 
named the alkaloid and showed that it produced sleep in dogs. Sertumer tried his new 
compound out on his friends, at 10 times a modem recommended dose, reminding one of 
the aphorism that "A man should choose his enemies more carefully than his friends, 
because he will have them longer." Although the structure of this complex alkaloid was 
not proven until 1952, Robert Robinson suggested the correct structure in 1923, based on 
biosynthetic considerations. Robinson realized that a morphine-type structure could be 
obtained by rotation through 90° of the 1 -benzyl group of a tetrahydroisoquinoline such as 
reticuline followed by bond formation between the 2' position of the benzyl group and the 
10 position of the isoquinoline ring (Fig. 5). Tetrahydroisoquinolines, in turn, could be 
formed from two molecules of tyrosine. The tyrosine-derived rings form the stem and one 
wing of the final, rigid T-shaped morphine molecule. 

In addition to deducing the correct structure, Robinson also deduced a biosynthetic 
scheme, which transpired to be correct in the main, and unknowingly established the 
chemical relationship between the prosilient metabolite of the poppy and the structurally 
mundane peptides of the brain exhibiting a similar neuropharmacology. The first of these 
peptides was discovered by Hughes and Kosterlitz in 1975 (Hughes and Kosterlitz, 1975). 
Since then, many others have been isolated, acting at an increasing number of opioid 
receptors. The structural feature held in common by these various enkephalins, en- 
dorphins, and dynorphins is the presence of a tetrapeptide sequence, Try-Gly-Gly-Phe. 
Three opioid receptors are currently recognized, the u., 5, and k, each having its bevy of 
subtypes. Strangely, the pharmacology of morphine seems to be exerted largely via the u. 
receptor. Even more strangely, the function of these receptors is unclear, as the admin- 
istration of naloxone, an antagonist at all three types, is unassociated with deleterious 
consequences in laboratory animals. Despite this, the brain generates cascades of these 
three classes of peptides via the actions of various peptidases, all exhibiting pharmacolog- 
ical activities at one or more of the opioid receptors (Hollt, 1986). 

Evolution of higher animals was paralleled by the abridgement of considerable 
chemical ingenuity: Plants are better chemists than mammals. We, with our limited ability 
for postribosomal modification of proteins and peptides, achieve molecules with similar 
pharmacological activities to those of morphine by incorporating two unmodified aromat- 
ic amino acid residues into a polypeptide chain, spacing them with two glycine molecules 
to allow the aromatic rings to twist themselves into the appropriate T-shaped relationship 
needed to bind to the opiate receptors. Thus, from the pharmacological point of view, 
morphine is simply a modified dipeptide. The apparent lack of structural consonance 
between morphine and the endorphins and enkephalins of the central nervous system is a 
perceptual artifact induced by the limitations of representing three-dimensional structures 
on paper. In fact, both poppy and man achieve the same pharmacological end from the 
same starting materials. The difference resides in the sophistication and economy of the 
chemistry employed. Morphine can, therefore, serve as an important model for neu- 
ropharmacology and as a lesson that if problems in neuropharmacology are considered 



315 



94 



Ryan J. Huxtable 




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Neurotoxins in Herbs and Food Plants 95 

thrce-dimensionally, the rational relationship between apparently disparate observations 
may be made more evident. 



3.2. Neurotoxic Amino Acids in Plants 

Numerous unusual, nonproteinaceous amino acids are scattered through the plant 
kingdom. Examples include GABA, homoserine, or citrulline (Roy, 1981). Most are 
innocuous in the amounts likely to be ingested. A few are severely neurotoxic. In particu- 
lar, excitotoxins are found in a number of plants that mimic the actions of glutamate on the 
central nervous system. Glutamate is often added to foods as a flavor enhancer. It is the 
cause of the ill-named Chinese restaurant syndrome; ill-named because many foods rang- 
ing from canned Peruvian anchovies to Japanese sukiyaki contain levels of glutamate 
sufficient to precipitate the pounding headaches and lassitude of the syndrome. It is 
noteworthy that other excitotoxic amino acids, such as tricholomic and ibotenic acids, are 
also flavor enhancers. 

A number of tropical myeloneuropathies are known that are found in association with 
nutritional, environmental, and climatic factors (Roman et al., 1985). These conditions 
include peripheral neuropathies, Parkinsonism, dementia, and amyotrophic lateral scle- 
rosis. They all share a dietary factor as a precipitant. Although there is some dispute as to 
the nature of these factors, the bulk of evidence suggests that they are excitotoxins. 

Lathyrism is a disease caused by consumption of the seeds of Lathyrus species, such 
as L. sativus (chickling pea), L. clymenum, and L. cicera, all containing the excitotoxin, 
(3-N-oxalylaminoalanine (Fig. 3). The two major forms of the disease are osteolathyrism. 
affecting primarily the bones, and neurolathyrism. The latter is a progressive, degener- 
ative motor neuron disease leading to spastic paraplegia (Spencer and Schaumburg, 
1983). Pyramidal tracUesions cause damage to upper motor neurons, leading to increased 
motor tone and exaggerated responses to muscle stretch (Spencer et al., 1986, 1987). 
There is increasing difficulty with walking, sufferers ultimately being reduced to crawling 
(Ludolph et al., 1987). 

At one time, lathyrism was endemic in Europe and much of Africa and south central 
and southeast Asia. Although the geographic area in which it occurs is shrinking, the 
disease still occurs with high prevalence in Bangladesh, India, and Ethiopia (Tekle 
Heimanot et al., 1990). For India, 100,000 cases were reported in 1975 in men between 
the ages of 15 and 45 (Liener, 1974). This is probably an underestimate. In affected areas, 
the incidence can be 2.5% of the population (Ludolph et al., 1987). An unusual outbreak 
occurred in Europe in the Second World War in German forced-labor camps, when 
malnourished inmates were given Lathyrus flour to eat (Gardner and Sakiewicz, 1963). 

L. sativa seeds are high in protein (28%), and the plant flourishes in the absence of 
irrigation or fertilization. It thus becomes an irresistible source of food under famine 
conditions. Lathyrism develops after weeks or months of seed consumption. The ex- 
pression of the disease is, therefore, polyfactorial, involving protein and calorie malnutri- 
tion, in addition to the consumption of L. sativa. 

Fed to cynomolgus monkeys, Macaca fascicularis. (3-N-oxalylaminoalanine pro- 
duces corticospinal dysfunction in the absence of extrapyramidal lesions, analogous to 
that seen in humans consuming L. sativus (Kurland. 1988; Spencer et al., 1986; Watkins 
et al., 1966). 



317 



96 Ryan J. Huxtable 

To date, attempts to breed a toxin-free variety of Lathyrus have not been successful. 
In areas where rice and wheat supplant Lathyrus as a staple in the diet, the incidence of 
neurolathyrism falls. 

Vicia (vetch) species contain a neurolathyrogen, 3-cyanoalanine (Fig. 3) along with 
its -/-glutamyl derivative. Both compounds produce hyperactivity and convulsions in 
weanling rats (Ressler et al., 1969). As Vicia seeds sometimes contaminate Lathyrus 
seeds in India, this compound may contribute lathyrism in that country. Although the 
metabolism of 3-cyanoalanine does not appear to have been studied, it is possible that it 
enters the brain followed by oxidation of the cyano grouping to yield the excitotoxic 
amino acid, aspartate. 

Another neurotoxin-induced degenerative motor disease occurs in the western Pa- 
cific (Garruto and Yase. 1986; Kurland, 1988; Rowland, 1987; Spencer et al.. 1987; 
Whiting, 1963; Zhang et al.. 1990). The neurotoxin is probably P-N-methylaminoalanine 
(Fig. 3), a constituent of locally consumed cycad seeds. The well-studied condition it 
causes has elements of amyotrophic lateral sclerosis and Parkinsonism with dementia. The 
disease has three geographic loci: It occurs among the Chamorros in the Miriana Islands, 
including Guam, the Auyu, and Jakai of west New Guinea, now part of Indonesia, and 
among the Japanese of the Hobara and Kozagawa districts of the Kii peninsula on the main 
island of Honshu. The rates of amyotrophic lateral sclerosis are the highest in the world in 
the affected areas of New Guinea, being 150 times higher than the rate for the United 
States. Forty years ago, the incidence in the Marianas was almost as high (Kurland, 1988). 
The disease is familial, but not genetic. In the Marianas and Japan, behavioral and cul- 
tural changes have led to a decrease in the incidence of disease (Garruto and Yase, 1986). 
It is noteworthy that no increase in amyotrophic lateral sclerosis or Parkinsonism/ 
dementia has occurred among the large number of U.S. armed forces who has been 
stationed on Guam since the war (Brody et al.. 1979). Conversely, Guamian-bom Cha- 
morros who move to the United States aftenhe age of 18 carry an increased risk of 
amyotrophic lateral sclerosis, which may appear with a latency of 30 years (Brody et al., 
1979). 

Pacific amyotrophic lateral sclerosis is similar to the condition originally described 
by Charcot and is also associated with the presence of neurofibrillary tangles in the brain 
and spinal cord (Rowland, 1984, 1987). Of Chamorros dying of nonneurological causes, 
up to 70% show neurofibrillary tangles (Anderson et al., 1975; Chen, 1981; Chen and 
Yase, 1985). Pacific amyotrophic lateral sclerosis differs from lathyrism in that lesions 
occur simultaneously in the upper and lower motor neurons. As well as degeneration of 
the anterior hom cells in the spine, there is degeneration of peripheral motor axoif?, 
leading to neurogenic muscle atrophy (Spencer et al., 1987). 

The disease is associated with, and in all likelihood caused by, consumption of flour 
prepared from the cycad palm, Cycas circinalis, and related species, such as C. revoluta. 
The latter species, false sago palm, is common in the affected areas of Japan, where it is 
known as sotetsu. These plants should not be confused with the other sago palm, Metrox- 
ylon sagu. source of the once common but increasingly unfamiliar sago pudding of 
England (Gilks, 1988). 

In Guam, C. circinalis has been a traditional food source. During the wartime 
Japanese occupation of the Marianas, there was an increased consumption of cycad flour, 
combined with undernutrition of the population. With the changes in life-style brought 
about by the postwar American military presence on Guam, the use of cycads has fallen 
dramatically. However, in Japan, cycad seeds are still used in traditional medicine in the 
Kii peninsula (Spencer et al., 1987). 



318 



Neurotoxins in Herbs and Food Plants 97 

Recently, a method has been developed allowing analysis of P-N-methyiamino- 
alanine in the low picogram range (Duncan and Kopin, 1989). This has allowed confirma- 
tion of the presence of the toxin in a number of Cycas species. In seeds from C. circinalis. 
levels of 8.5 u,mol/g dry weight were found, and levels of 2.7 and 2.5 u.mol/g were found 
in seeds of C. revoluta and C. media, respectively. Flour from Cycas seeds contained up 
to 1.2 u,mol/g. 

Pacific amyotrophic lateral sclerosis has been suggested to be caused by metal 
intoxication (Duncan et al., 1988; Garruto and Yase, 1986; Garruto et al., 1988), but this 
theory has been increasingly discounted. 

B-N-Methylaminoalanine is unusual among excitatory amino acids in not being 
acidic. This suggests that the actual toxin may be an acidic metabolite. Cynomolgus 
monkeys given the acid by gavage develop neurological deficits within 2-12 weeks 
(Spencer, 1987). 

Both B-N-methylaminoalanine and B-N-oxalylaminoalanine are toxic to neuronal 
cell cultures (Nunn et al.. 1987; Spencer et al., 1987), and both produce seizures in 
neonatal rodents (Olney et al., 1976; Polsky et al., 1972). The effects of S-N-meth- 
ylaminoalanine take several hours to develop, suggestive of metabolic activation. Further- 
more, bicarbonate is required as a cofactor in the expression of B-N-methylaminoalanine 
toxicity in in vitro neuronal cell cultures (Weiss and Choi, 1988). It has been suggested 
that toxicity is a result of an acidic carbamate grouping forming in solution by reaction of 
the amine function with bicarbonate (Nunn et al., 1991). The carbamate is ster- 
eochemically similar to the neurotoxin, N-methyl-D-aspartate. The formation of carba- 
mates as transient species in solution in the presence of carbon dioxide has been convinc- 
ingly established by NMR (Morrow et al., 1974; Nunn and O'Brien, 1989). However, 
it is problematic whether such species are involved in the neurotoxicity of B-N- 
methylaminoalanine. Amino acids such as alanine are not neurotoxic, although they also 
form carbamates. Indeed, a-carbamates must be the normal form in which free amino 
acids and the N-terminal of peptides and proteins exist. Furthermore, it takes several hours 
for the toxicity of B-N-methylaminoalanine to be manifested in cell cultures, although a- 
carbamates form rapidly (Morrow et al., 1974). 

Intracisternally administered B-N-methylaminoalanine in rats produces a lowering in 
norepinephrine levels in the hypothalamus without affecting the levels of other mono- 
amines (Lindstrom et al. , 1990). Intranigral injections of B-N-oxalylaminoalanine similar- 
ly lower norepinephrine levels in the hippocampus. 

Neurochemically, both B-N-methylaminoalanine and B-N-oxalylaminoalanine 
are agonists at glutamate receptors, the latter having the higher potency (Spencer et 
al., 1987). The action of B-N-oxalylaminoalanine is blocked by the A 2 (quisqualate) 
and A 3 (kainate) antagonist, cw-2,3-piperidine dicarboxylic acid. The action of B-N- 
methylaminoalanine is blocked by the A, (N-methyl-D-aspartate) antagonist, D-2- 
amino-7-phosphonoheptanoic acid. The D-stereoisomers of the plant amino acids are 
without toxicity in vivo and without potency at the glutamate receptor (Nunn et al., 1987; 
Spencer et al., 1987). 

An algal excitotoxin, domoic acid (Fig. 3), caused an outbreak of poisoning in 
Canada recently (Snodgrass, 1990; Teitelbaum et al., 1990). Domoic acid was first 
isolated from a Japanese seaweed, Chondria armata (Takemoto, 1978), but was subse- 
quently found to be elaborated by a seaweed, Nitzschia diatomea, growing around Prince 
Edward Island. Mussels grazing on the seaweed were, in turn, consumed by humans. 

Domoic acid has high affinity for the kainate subtype of the glutamate receptor. 
Symptoms of domoic acid intoxication included neurological dysfunction and memory 



319 



98 Ryan J. Huxtable 

and motor deficits. Neuronal necrosis was apparent on autopsy in the hippocampus and 
amygdala. Intoxication went through two stages: an initial stage involved neural hyperex- 
citation, presumably due to the direct neuroexcitatory actions of domoic acid, while the 
subsequent stage involved loss of function in neural systems suffering excitotoxic degener- 
ation. 

Again, however, other factors appear to be involved in the expression of domoic acid 
toxicity, as no dose-response relationship could be established between the amount con- 
sumed and the severity of symptoms (Snodgrass, 1990). The quantity of protein in the diet 
may affect absorption of domoic acid. 

Other neurotoxic amino acids in plants include 2,4-diaminobutyric acid and its y- 
oxalyl derivative in Lathyrus and Vicia aurantica, and 3-nitropropionate in Indigofera 
endecaphylla (Fig. 3) (Roy, 1981). 

The latter compound causes lesions of the lateral caudate putamen on i.p. injection in 
mice (Gould and Gustine, 1982). It is an irreversible inhibitor of succinate dehydrogenase 
and a competitive inhibitor of fumerase. Nitropropionate therefore blocks energy produc- 
tion by the tricarboxylic acid cycle and disrupts the metabolism of neurotransmitter amino 
acids. The glucose ester of 3-nitropropionate and the glucoside of 3-nitropropanol (mis- 
erotoxin) are present in other legumes of the Astragulus and Coronilla genera, and are 
also produced by some fungi, such as Aspergillus and Penicillium. These nitro com- 
pounds are major agricultural problems (Williams and James, 1978). 

Kainic acid, an important neurochemical tool, was isolated from the Japanese sea- 
weed, Digenia simplex (Takemoto, 1978). Hundreds of tons of this plant per year are used 
as an ascaricide. Two other excitotoxins have been isolated from Japanese mushrooms: 
tricholomic acid from Tricholoma muscarium and ibotenic acid from Amanita strobilifor- 
mis and other Amanita species (Takemoto, 1978). The former was used by as a food and as 
a fly killer. These two acids are 20 times more potent than glutamate as flavor enhancers. 
That so many excitotoxic amino acids have been isolatedfrom Japanese plants must be 
considered an ethnobotanical rather than a botanical phenomenon. 



3.3. Neurotoxic Monoterpenes and Terpenoids 

Many medical and culinary plants contain terpenes and essential oils that yield a 
characteristic odor and taste. The fascinating history of the use of such plants can be 
traced in various monographs (Andrews, 1984; Wheelwright, 1974). 

Neurotoxic terpenes tend also to be toxic to other organ systems. Thus, oil of 
pennyroyal, from Mentha pulegium, is often used in attempted abortion. The active 
terpene, pulegone (Fig. 6), produces hepatic and renal failure, in addition to its effects on 
the central nervous system. These include hallucinations (Early, 1961). In rats, pulegone 
causes a neuropathy characterized by lesions in the cerebellum (Olsen and Thorup, 1984). 

One of the oldest and most widely distributed psychotomimetic plants is Cannabis 
(Schultes and Hofmann, 1980). This has been cultivated for so long that its botanical 
origins are unclear. Some think the numerous cultivars comprise one species. Cannabis 
saliva, while others hold that it is a mixture of the three species, C. sativa, C. indica, and 
C. ruderalis. Cannabis is a plant of polyvalent uses, serving as the source of hemp, 
marijuana, and an edible oil. Cultivars have been developed to increase selectively the 
quality of each of these products. 



320 



Neurotoxins in Herbs and Food Plants 



99 



<*> 



Mem hot 





Camphor 



CH, 



H,C -CH, 



Pinene 







yv 



CjH,, H 3 C CH ) 



Thujone 



H,c -CH. 



A 9 tetrahydrocannabinol 



Pulegone 



FIGURE 6. Some neurotoxic monoterpenes. 



In marijuana, the major psychoactive substance is A 9 -tetrahydrocannabinol (Fig. 6) 
(Hollister, 1986). This appears to be a combination of a monoterpene with an olivetol 
fragment. It acts at a specific receptor in the brain, attenuating dopaminergic activity 
(Howlett et al., 1990; Martin, 1986). The high liposolubility of cannabinol leads to the 
economical phenomenon of reverse tolerance. As the material accumulates in the central 
nervous system, less is needed to precipitate a "high." Cannabinoids have antinociceptive 
and analgetic activities worthy of therapeutic exploitation. The study of synthetic and 
semisynthetic analogs of the natural cannabinoids has spawned an enormous volume of 
work (Razdan, 1986). 

The wormwood, Artemisia absinthium, has been used in Europe-and North America- 
as a sedative. Oil of wormwood was an ingredient in the bright green, alcoholic, and 
hallucinogenic drink, absinthe, banned since the early part of the century. The active 
principle is the monoterpene, thujone (Fig. 6), which probably acts in the central nervous 
system at the same receptor as A 9 -tetrahydrocannabinol (del Castillo et al., 1975). Thu- 
jone produces convulsions in rats at 40 mg/kg, and death at 120 mg/kg (Tyler, 1982). In 
mice, the LD 50 (s.c.) is 134 mg/kg (Budavari, 1989). 

The drinking of absinthe has been fixed on numerous impressionist canvasses, in- 
cluding paintings by Manet, Degas, Toulouse-Lautrec, and van Gogh. In this ritualistic 
activity, an emerald-green liquid was poured slowly over sugar held in a perforated spoon 
and diluted into water. The translucent green was replaced by an opaque white as the 
essential oils held in alcoholic solution precipitated out (Vogt, 1981). Perforated spoons 
can still be seen in certain European cafes, but these days the purpose is to prevent their 
theft for free-basing cocaine. The reputation that absinthe had can perhaps be gauged by a 
quotation from a 1916 letter of Aldous Huxley (1969), ". . . he turned deathly pale and, 
rushing out of the room, proceeded to be sick . . . And that is what comes of drinking 
absinthe before dinner." In this case, however, Huxley suspected the drink had been 
adulterated with methanol. 

An extract of A. absinthium is extraordinarily bitter, due to the content of absinthin, 
which has a taste threshold of one part in 70,000. One recalls the nurse in Romeo and 
Juliet who smeared wormwood on her nipples to wean Juliet. The plant has a long medical 



321 



100 Ryan J. Huxtable 

history. The common name derives from its use in treating intestinal worms, but it was 
additionally used as a febrifuge and aphrodisiac, the latter action perhaps not unrelated to 
the popularity of absinthe. 

Absinthe drinking was believed to induce a mood of exaltation. It was used by many 
artists and writers, including Baudelaire, van Gogh, Ernest Dowson, and Verlaine, to 
enhance their artistic perceptions. The writer, Dawson, refers to "the curirjs bewilder- 
ment of one's mind after much absinthe," and it appears to have been taken as an 
intellectual or creative stimulant. Prolonged consumption, however, is associated with 
addiction, auditory and visual hallucinations, and hyperexcitability. The condition was 
first recognized in the 1850s. 

Thujone is found in other genera apart from Artemisia, including species of Salvia, 
Tanacetum. and Thuja (hence the name) (Albert-Puleo, 1978). It constitutes 40-90% by 
weight of oil of wormwood (Simonsen. 1949). Thujone is a convulsant, as are the related 
monoterpenes, camphor, menthol, and pinene (Fig. 6) (Goodman and Gilman, 1958; 
Sollmann, 1948). Their lethality, however, is low. For camphor, the minimum lethal dose 
in rats is 2.2 g/kg. 

A case has been made that van Gogh suffered from "terpene toxicosis" (Arnold, 
1988). He was an habitual imbiber of absinthe, and during one period of abstinence had to 
be restrained from drinking turpentine. Arnold (1988) points out that turpentine contains 
monoterpenes such as pinene, and suggests this was an attempt at self-medication of 
withdrawal symptoms. This raises the further possibility that van Gogh, and perhaps other 
painters, suffered an occupational addiction caused by the fumes of the turpentine to 
which they were so frequently exposed. 

Part of the attack launched in the columns of medical journals was undoubtedly 
fueled by the bohemian associations of absinthe drinking. Exaggerated claims about the 
toxicity of absinthe were made, along the lines of the attacks on "demon" alcohol or the 
supposed psychosis-precipitating effects of marijuana during Anslinger's 1930-1962 ten- 
ure of the U.S. Bureau of Narcotics and Dangerous Drugs. One writer claimed that 
absinthe was an ignoble poison that brutalized its votaries and made drivelling idiots of 
them (Beach, 1860). On the other side, it was early argued that the symptoms of ab- 
sinthism were no different than the symptoms of alcoholism — sleeplessness, tremors, 
hallucinations, paralysis, and convulsions (Anonymous, 1869). 

Dose calculations can illuminate discussion on the cause of absinthism. How much 
thujone was present in absinthe? Steam distillation of wormwood yields 0.27-0.40% of a 
bitter, dark-green oil (Guenther, 1952). In a typical recipe for absinthe, 2.5 kg of worm- 
wood were used in preparing 100 liters of absinthe (Arnold, 1989). Typically, 1.5 ounces 
were consumed (diluted with water) per tipple (Vogt and Montagne, 1982). This is 
equivalent to 4.4 mg of wormwood oil per drink, or between 2 and 4 mg of thujone. This 
is far below the level at which acute pharmacological effects are observed. Even chronic 
administration of 10 mg/kg thujone to rats does not alter spontaneous activity or condi- 
tioned behavior (Pinto-Scognamiglio, 1968). The literature on the pharmacology of thu- 
jone is, to put it bluntly, second rate, and conclusions as to its effects have been extrapo- 
lated far beyond the experimental base. In fact, the supposed chronic neurotoxicity of 
thujone is by no means well established. Even allowing that a condition not identical to 
alcoholism existed, agents other than thujone in absinthe could have been responsible. 
The amount of wormwood used was highly variable. Many other herbs and flavorants 
were used, including angelica, marjoram, hyssop, mint, fennel, star anise, and calamus. 
The latter plant. Acorus calamus, also has the reputation of being psychedelic, due to its 



322 



Neurotoxins in Herbs and Food Plants 101 

content of asarone (Hoffer and Osmond, 1967). Because the visual esthetics of absinthe 
drinking were an important pan of the ritual, manufacturers did not hesitate to adulterate 
their product to obtain the correct degree of emerald green, and the appropriate ap- 
pearance of a white precipitate on dilution with water. Typically, the shade of green was 
"corrected" with copper sulfate, and the degree of opalescence adjusted by the addition of 
antimony chloride. Other adulterants included indigo, tumeric, and aniline green. Meth- 
anol has been found in absinthe, and some of the neurological effects of absinthe drinking 
have been ascribed to this (Walton et al., 1986). 

Thujone is still to be found in low amounts in drinks such as vermouths, chartreuse, 
and benedictine, although no addiction comparable to absinthism has been reported. 
Indeed, the word vermouth is but a cognate of the German Wermuth, or wormwood. Other 
drinks, such as raki, arrack, retsina, and ouzo, contain essential oils. 

The true nature and cause of absinthism is one of those mysteries that, like that of 
Edwin Drood, is unlikely ever to be solved. But one can suspect that absinthism was a 
multifactorial complex of conditions produced partially by adulterants and other ingre- 
dients added to the drink, partially by alcohol, and partially by imagination. 

The related terpene, camphor (Fig. 6), derives from the tree Cinnamomum cam- 
phora, indigenous to Japan and Taiwan. Camphor is also a stimulant and convulsant. 

The euphoria produced in cats by the odor of catnip, Nepeta cataria. is well known. 
Mood elevation and euphoria also occurs in humans smoking the plant (Jackson and Reed, 
1969). The effect, however, is claimed to be proportional to the user's expectations. The 
activity, at least in cats, is due to nepetalactone (Bates and Sigel, 1963). 



3.4. Other Plant Neurotoxins 

Other volatile substances add flavor and spice to numerous culinary herbs, and some 
of these are centrally acting. Nutmeg, Myristica fragrans, once so important that its 
geographic source was known simply as the Nutmeg Islands, contains hallucinogenic 
aromatic ethers such as elemicin (Fig. 7) (Efron etal., 1979; Faguet and Rowland, 1978). 
The structure is reminiscent of mescaline (Fig. 1). The hallucinogenic action of these 
ethers may involve their conversion to amphetamine derivatives via oxidation and anima- 
tion, although this is unproven (Shulgin et al., 1979). Other spices, such as saffron, 
fennel, dill, anise, and parsley, contain similar psychoactive ethers, including safrole, 
eugenol, and myristicin (Fig. 7). 

Valeriana officinalis has been used as a sedative for centuries. Controlled trials have 
shown its efficacy in humans. Its activity is thought to be due to the sesquiterpenes 
valeranone, valerenol, and valerenic acid (Hendriks etal., 1981; Leathwood et al. , 1982). 

Piper methysticum is used in the south Pacific to make the drink known as kava, or 
kava-kava (Ford, 1979). The use of this mild relaxant revolted early missionaries, as its 
preparation involved the chewing of the root by women and children followed by collec- 
tion of the expectorate. The active principles are the dinydropyrones, methysticin and 
kawain (Fig. 7) (Klohs, 1979). Methysticin antagonizes strychnine-induced and elec- 
troshock convulsions, and potentiates pentobarbital-induced sleeping time. 

Clove cigarettes, prepared from mixtures of tobacco and Eugenia caryophyllata: are 
popular among segments of the American population for the marijuana-type high engen- 
dered. The active ingredients are probably eugenol (Fig. 7), acetyleugenol, and related 



323 



102 



Ryan J. Huxtable 



<^/^^°^° 



■%/■ 




Kawain 



OCH, 



H 3 CO 




R 1 =. h R 2 = H Eugenol 

R., - CH 3 R 2 = -OCH 3 Elemicin 




OCH, 




R - OCH3 Myristicin 
R =» H Safrole 



Methysticin 

FIGURE 7. Some neurotoxic components of essential oils 



compounds. Deaths have resulted fronuheir. use. Cloves, however, have a_long_culinary 
and medical history, and present little hazard on ingestion. 

Chicory, Chicorium intybus, has been used as a coffee extender or coffee substitute. 
It adds its characteristic flavor to New Orleans coffee, where it is viewed as a specialty. In 
England, after the war, extract of chicory was inflicted as a coffee substitute on a deprived 
public. A taste of chicory to those so exposed conjures up nothing but a recollection of 
drabness and perpetual hunger. Such is the importance of a point of view. 

Unlike coffee, chicory is sedative. Indeed, it counteracts the stimulation induced by 
caffeine. The active principle is probably lactucin (Max, 1988b). 

One species of the maligned yew, toxic and, like cypress, associated with death and 
graveyards, has recently come to clinical prominence because of the efficacy of the 
alkaloid, taxol, as an antineoplastic agent. Taxus brevifolia has for years been cleared 
from American forests as a slow-growing, uneconomic trash tree. Now, however, frantic 
efforts are being made to increase the supply (Chase, 1991). Taxol exerts its chemothera- 
peutic effect by inducing microtubule assembly and disrupting cell proliferation. Taxol- 
induced microtubular assembly in dorsal-root ganglion cells appears to be responsible for 
the sensory neuropathy that occasionally accompanies its chemotherapeutic use (Lipton et 
al., 1991). 

Neem oil is obtained from the seeds of the Indian tree, Melia azadirachta L. 
(Azadirachta indica A. Juss). Although its garlic-like odor limits its culinary use, the oil is 
widely used in the indigenous, traditional medicines of India, including the Ayurvedic and 
Unani. It is, however, toxic, producing a syndrome similar to Reye's in children (Sinniah 
et al., 1989). In experimental animals, it is neurotoxic (Gandhi et al.. 1988). The toxic 
agent may be a monounsaturated fatty acid. 



324 



Neurotoxins in Herbs and Food Plants 103 

The convulsant, picrotoxinin, in the form of the complex, picrotoxin, is obtained 
from the east Indian shrub, Cocculus indicus (Anamirta cocculus). Ethnopharmaco- 
logically, it was used as a fish poison. Like the alakaloid, bicuculline, picrotoxinin acts as 
a GABA antagonist. However, despite its spelling, picrotoxinin contains no nitrogen. 

Other important plant neurochemicals include capsaicin, the pungent principle in 
peppers (Capsicum spp.) (Buck and Burks, 1986). 

Under certain conditions, thiocyanates derived from plants can cause neuropathies 
(Roman et al., 1985). Cassava (Manihot esculenta) is widely consumed throughout the 
tropical regions, over 300 million people relying on it as a principal source of calories. In 
the intensely glutinous form of tapioca, it is even known in England, where it is fed to 
resisting school children. Cassava has a high content of the cyanohydrin glycoside, 
linamarin, and has to undergo a labor-intensive washing procedure to make it palatable. 
Under famine conditions, this washing procedure may be abbreviated, and forms of 
cassava higher in cyanide may be used. Following consumption, the cyanide is converted 
to thiocyanate, which produces a variety of health problems, including an ataxic neuropa- 
thy. In some cassava-induced outbreaks of ataxic neuropathy in Africa, incidences as high 
as 34 per 1000 population have occurred. Plasma thiocyanate levels are extremely high in 
affected individuals. Compared to control levels of 1 u.mol/1, levels of 1 14 u.mol/1 were 
found in a Nigerian outbreak, and levels ranging from 298 to 336 u.mol/1 in an outbreak 
in Mozambique (Roman et al., 1985). 

As with other plant neurotoxicities, consumption of improperly prepared cassava is a 
necessary but insufficient condition for the disease to develop. Poisoned individuals not 
only show high plasma levels of thiocyanate, indicating high dietary intake of cyanide, 
but also low urinary levels of sulfate, indicating low dietary intake of sulfur amino acids. 
This occurs during periods of food shortage and has been observed in Mozambique, 
Nigeria, and Tanzania (Cliff er al., 1985). Neighboring populations with the same intake 
of cyanide combined with normal intake of sulfur amino acids do not develop ataxic 
neuropathy. Sulfur is needed for detoxification of cyanide via conversion of thiocyanate. 

Cassava is not unique in containing cyanogenetic glucosides. These are present in 
yams, beans, com, millet, apples, peaches, almonds, and numerous other fruits. Indeed, 
cyanide is usually described by those who can smell it (80% of the population) as having 
the odor of almonds (Balbaa et al., 1973). In fact, of course, it is the other way around; 
almonds smell of cyanide. The almond tree, Prunus amygdalus, contains the cyanohy- 
drin, amygdalin. The ataxic neuropathy produced by cassava is, therefore, a cultural 
problem, brought about by over-reliance on a single cyanogenetic plant for subsistence. 



4. CONCLUSIONS 

Neurotoxicity from plant metabolites is common outside of North America, western 
Europe, and a few other developed nations. Poisoning often results from a concatenation 
of circumstance, of which consumption of a neurotoxic plant is only one link in the chain. 
Climatic factors, such as drought, protein and calorie malnutrition, and economic and 
cultural factors, all combine in the expression of neurotoxicity. Economic factors are 
involved in the heavy reliance on one species, such as cassava, for nutrition or the inability 
to purchase fertilizers for the growing of nontoxic crops. Cultural and political factors 
were involved in the re-emergence in Europe of lathyrism and ergotism in German forced- 
labor camps during the Second World War, and in the heavy reliance of Cycas flour in the 



325 



104 Ryan J. Huxtable 

Mariana Islands during the Japanese occupation in the same war. As with the Cycas 
poisonings, there may be a long latency between exposure to environmental factors and 
the clinical expression of a disorder (Calne et al.. 1986). 

In countries having complex industrial economies, occasional epidemics of neurotox- 
icity occur, as in the recurrence of ergotism in France 40 years ago. However, neurotox- 
icity in more recent times is usually due to consumption of foods other than plants, as with 
the outbreak of domoic acid poisoning from contaminated mussels in Canada (although 
the mussels, in turn, obtained the toxin from a plant). Poisonings due to the deliberate 
consumption of psychoactive plants or chemical derived from them is common. Datura 
intoxication is well known in emergency rooms and poison control centers in North 
America. 

Fundamental to most cultures is the routine use of stimulants and depressants in 
pharmacological doses. In western societies, such use is so pervasive that many do not 
consider such substances to be drugs. But how many among us could get through the 
diurnal cycle with its ephemeral anxieties and pressures without the assistance of coffee, 
tea, tobacco, alcohol, or cocoa, or their illegal cousins marijuana, cocaine, or heroin? 

Plant neurotoxins have been of inestimable value to pharmacology. The toxicities of 
one age become the tools of progress of another. Ergot has changed from being a feared 
and fearsome disease into the source of valuable pharmaceutical agents. Plant excitotoxins 
are being used to unravel the complexity of amino acid receptors in the brain, cocaine and 
reserpine were tools in the elucidation of sympathetic function, and caffeine in the parallel 
study of purinergic receptors. The value to pharmacology of muscarine, nicotine, mor- 
phine, atropine, and a Pandora's box of other plant neurotoxins is obvious to any pharma- 
cologist. 

The neurotoxicities of plant products may mimic or model other natural processes. 
This is an increasingly important aspect of research on these compounds. Thus, excito- 
toxin-induced neuronal degeneration mimics diseases such as Alzheimer's or Parkinson's 
disease, and may model the process of aging in the central nervous system (Calne et al., 
1986). 

In the main, knowledge of these valuable compounds has stemmed either from the 
health problems generated by the plants containing them, or by investigation of plants 
used ethnobotanically, i.e., for specific cultural uses. What is perhaps not so obvious is 
that progress in the neurosciences continues to depend on the study of novel natural 
products. For such progress to continue, the ethnobotanical knowledge of vanishing 
cultures must be recorded (e.g., see Schultes and Raffauf, 1990) and the accelerating rate 
of human-induced extinction of plant species slowed. 

Man is a poor organic chemist compared to nature, and nature will continue to inspire 
our synthetic efforts. Within the last 30 years, kainic acid was obtained from an obscure 
alga, and the potent antineoplastic dolastatins from the insignificant sea hare, Dolabella 
auricularia (Pettit et al.. 1982). The clinically important anticancer agents, vincristine 
and vinblastine, were isolated from the unconsidered Madagascar periwinkle, Cathar- 
anthus roseus. examined because of its ethnomedical use. Yet the Malagasy Republic on 
Madagascar encompasses one of the most degraded ecosystems on the planet, one in 
which numerous unstudied plants have become extinct. From a purely utilitarian point of 
view, no species can be considered to be without value; a useless species is one for which 
a use is waiting to be discovered, not one without use. Thus, Ginkgo biloba, a plant that 
fortuitously escaped the extinction of all other species in its family, has proven to be the 
source of unique pharmacological agents (Max, 1987). We can only wonder at what never- 



326 



Neurotoxins in Herbs and Food Plants 105 

to-be discovered pharmacological agents have been lost forever with the heedless and 
accelerating extermination of plant species over the last few decades. 



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Reprinted from ANNALS OF INTERNAL MEDICINE Vol 117, No 2 15 July 1992 

Printed in USA. 



The Myth of Beneficent Nature: The Risks of Herbal Preparations 



In 1976, in Tucson, Arizona, Dr. Alfred Stillman, a 
gastroenterologist, saw a 6-month-old girl with ascites 
and distended abdominal veins. Two weeks earlier, the 
child had had a normal pediatric examination. On ques- 
tioning, the mother divulged that in the intervening pe- 
riod the child had been given a considerable quantity of 
a commercially available herbal tea. We showed this tea 
to be from the plant Senecw longilobus, commonly 
known as thread-leafed groundsel, and to contain hepa- 
totoxic pyrrolidine alkaloids (1). Needle biopsy spec- 
imens confirmed a diagnosis of veno-occlusive disease 
and the subsequent development of cirrhosis. At first, 
this appeared to be an isolated case of poisoning, and 
the distributor voluntarily stopped selling the tea. A few 
months later, however, a 9-week-old boy was diagnosed 
with veno-occlusive disease at another hospital in Ari- 
zona. He had also been given an herbal tea, which had 
been sold, in this instance, by a pharmacist. Botanical 
identification and chemical analysis showed that this tea 
also derived from alkaloid-rich S. longilobus. In this 
case, the child died (2). Subsequently, other cases of 
human intoxication from Senecio species were discov- 
ered (3, 4). Because Senecio teas have been used ex- 
tensively for many years in the western United States, 
many other cases have probably gone unrecognized. 

Problems have surfaced with several other commer- 
cially available herbs. In this issue of Annals, seven 
cases of hepatitis resulting from the use of Teucrium 
chamaedrys (germander) are reported from France (5). 
This plant, in the mint family, is one of the few in my 
southwestern garden ignored by the rabbits and ro- 
dents. There is good reason for this: Teucrium contains 
noxious diterpenoid compounds that act as antifeeding 
agents. It is not easy to estimate exposure to Teucrium. 
My local pharmacy sells two types of Teucnum cap- 
sules, one for weight loss and one for anal pruritus. It 
has been reported that Teucrium is also sold in North 
America in herb stores mislabeled as another plant, 
Scutellaria, commonly called skullcap (6). Scutellaria is 
also sold under incorrect designations in the United 
Kingdom (7). It is unclear whether the two cases of 
skullcap poisoning, including one death, reported from 
the Riks Hospital in Oslo, Norway, in 1991, were due 
to Scutellaria, Teucnum, or some other herb. 

This underscores the importance of botanical identi- 
fication of herial preparations involved in poisoning 
cases. Too often, investigators assume the plant is what 
the packet claims (8), as in a recent case of fetal expo- 
sure in Switzerland (9-11). A 5-day-old girl was diag- 
nosed with veno-occlusive disease, dying 4 weeks later. 
She had been exposed to pyrrolizidines in utcro because 
of her mother's persistent use of an herbal tea. Relying 
on the listed ingredients, the investigators attributed 



poisoning to a plant, coltsfoot, but also claimed to have 
chromatographic evidence of an alkaloid not found in 
this species (9). Botanical analysis of a tea sample by 
another laboratory showed the presence of two pyr- 
rolizidine-containing plant species. 

Unfortunately, reports of herbal poisoning, such as 
the one appearing in this issue of Annals, are not un- 
usual. The more that such cases of poisonings have 
been looked for, the more they have been found (12). 
Of particular concern is the widespread use of prepara- 
tions containing one or more of the various species and 
hybrids of Symphytum (comfrey) (4, 13). Comfrey 
leaves are consumed in the form of salads, teas, and 
various herbal preparations. Comfrey is also rich in 
hepatotoxic pyrrolidine alkaloids. The highest levels 
occur in the roots, yet capsules of powdered root are 
widely sold in the United States as digestive aids, to be 
taken with each meal. A case of veno-occlusive disease 
of the liver has been reported in a woman who used 
such a preparation for 4 months (14). Sale of Symphy- 
tum is banned in Germany (15), and sale of Symphytum 
species and varieties containing the most toxic of the 
comfrey alkaloids are banned in Canada, but they are 
still freely sold in the United States. 

Although health problems from herbs can result from 
contamination, adulteration, and misidentification (8), 
most cases of poisoning probably result from the natural 
chemistry of the plants used. Susceptibility to poisoning 
can also vary among individuals for several reasons, 
including gender, age, state of health, and the concom- 
itant use of other drugs. For example, certain anticon- 
vulsants increase the toxicity of pyrrolizidine alkaloids. 
Among one group of Indians poisoned by the herbal use 
of Heliotropium, the two who died were taking phe- 
nobarbital for epilepsy (16). Cultural traditions can also 
increase susceptibility (12). Along the Mexico-United 
States border, for example, newborn babies may be 
given herbal teas to hasten the expulsion of material 
they may have swallowed in utero. 

A considerable mythology has arisen around herbs. 
For example, the medieval doctrine of signatures held 
that a beneficent creator would not expose us to ills 
without also supplying remedies. The appropriate plant 
for a remedy could be identified by some similarity, or 
"signature," between the plant and the ailment. Thus, 
it was believed that Pulmonana, could, as its name 
suggests, be used for lung diseases because the broad 
speckled leaves resemble the lungs. In a transmuted 
form, belief in this doctrine of signatures persists today. 
However, the reality is that plants elaborate the chem- 
icals found within them for their own purposes and not 
for ours. Plants have evolved in the presence of con- 
tinual assault from animals, insects, parasites, and bac- 



15 July 1992 • Annals of Internal Medicine • Volume 117 • Number 2 165 



331 



teria and have survived by developing sophisticated 
chemical defenses (17). A Victorian poet talked of "na- 
ture red in tooth and claw," but the truth is that it is 
the green rather than the red in nature that poses the 
greatest threat. Many more people in North America 
are killed or injured by plants than by animals, yet the 
herb industry in the United States is largely unregu- 
lated, and there are no requirements to demonstrate 
safety or efficacy in marketed products. 

Herbs associated with public health risks typically 
have nonspecific chronic effects, such as hepatitis, that 
are hard to associate with the cause. With pyrrol- 
idines, veno-occlusive disease is an early response that 
may not become clinically apparent. Over time, this 
disease may lead to cirrhosis of the liver, which may be 
ascribed to other causes, including ethanol consump- 
tion. In other instances, toxicity only occurs cumula- 
tively over time when a specific threshold is exceeded. 
With pyrrolizidine alkaloids, total doses of 11 mg/kg 
body weight or more cause pulmonary hypertension and 
right ventricular hypertrophy in rats, regardless of 
whether this dose is reached within 24 hours or 20 days 
(18). There is evidence that lower total doses are toxic 
to humans (10). 

If herbs present such risks and are so widely used, 
why are not more cases of poisoning reported? The 
probable answer is that such cases are not systemati- 
cally looked for. Cause-effect relations are rarely obvi- 
ous and have to be carefully sought. For example, to- 
bacco was smoked for centuries before an association 
with lung cancer was suspected. 

Even when herbal poisoning is suspected, investiga- 
tion is often not carried out properly. The literature is 
full of confusing reports, because proper botanical iden- 
tification was not done, proper chemical analysis was 
not done, or dose toxicity calculations were not made 
(8). What then should a physician advise patients who 
wish to use herbs sensibly? I have suggested the fol- 
lowing guidelines for reducing the risk of herbal use 
(12): 

1. Do not take herbs if pregnant or attempting to 
become pregnant. 

2. Do not take herbs if you are nursing. 

3. Do not give herbs to your baby. 

4. Do not take a large quantity of any one herbal 
preparation. 

5. Do not take any herb on a daily basis. 

6. Buy only preparations when the plants are listed 
on the packet (no guarantee of safety or correct- 
ness but better than nothing). 

7. Do not take anything containing comfrey. 

In conclusion, plants add color to our gardens, spice 
to our food, and interest and aesthetic delight to our 



lives (19). We use bergamot in Earl Grey tea; rosemary 
in sauces; and mint, nutmeg, cloves, and a herbarium of 
other plants, all of which can be toxic. People should be 
educated not to stop the use of plants but their abuse. 
Few things are risk free. 

Ryan J. Huxtable, PhD 
College of Medicine 
University of Arizona 
Tucson, Arizona 85724 

Requests for Reprints Ryan J Huxtable, PhD. Department of Pharma- 
cology. College of Medicine, University of Arizona. Tucson, AZ 85724. 

Annals of Internal Medicine. 1992;117:165-166. 



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7. MacGregor FB, Abernethy VE, Dahabra S, Cobden I, Hayes PC. 
Hepatotoxiciry of herbal remedies. BMJ. 1989;299:1156-7. 

8. Huxuble RJ, Awang DV. Pyrrolizidine poisoning [Letter). Am J 
Med. 1990;89:547-8. 

Roulet M, Laurini R, Rivier L. Calame A. Hepatic veno-occlusive 
disease in newborn infant of a woman drinking herbal tea. J Pedi- 
atrics. 1988:112:433-6. 

Huxuble RJ. The toxicology of alkaloids in foods and herbs. In: Tu 
AT, ed. Handbook of Natural Toxins: v. 7. New York: Marcel 
Dekker. 1992;[ln press|. 

11. Spang R. Toxicity of tea containing pyrrolizidine alkaloids. J Pedi- 
atr. 1989:115:1025. 

Huxuble RJ. The harmful potential of herbal and other plant prod- 
ucts. Drug Safety. 1990;5(Suppl 1): 126-36. 

Huxuble RJ, Luthy J, Zweifel V. Toxiciry of comfrey-pepsin prep- 
arations [Letter], N Engl J Med. 1986:315:1095 
Ridker PM, Ohkuma S, McDermott VW, Trey C, Huxuble RJ. 
Hepatic venocclusivc disease associated with the consumption of 
pyrrolizidine-containing dietary supplements. Gastroenterology. 
1985:88:1050-4. 

Tyler VE. Plant drugs in the twenty-first century. HerbalGram. 
1987;11:6-11. 

Mattocks AR. Chemistry and Toxicology of Pyrrolizidine Alkaloids. 
London: Academic Press; 1986:1. 

Huxuble RJ. Neurotoxins in herbs and plant foods. In: Isaacson 
RL. Jensen KJ5. eds. The Vulnerable Brain and Environmental 
Risks, v. 1. New York; Plenum Publishing; 1992 
Shubat PJ, Hubbard AK, Huxuble RJ. Dose-response relationship 
in intoxication by the pyrrolizidine alkaloid monocrotaline. J Toxi- 
col Environ Health. 1989:28:445-60. 

19. Max B. This and that: the essential pharmacology of herbs and 
spices. Trends Pharmacol Sci. 1992:13:15-20. 



9. 



10 



12. 



13 



14 



15 



Id 



17 



18 



© 1992 American College of Physicians 



166 15 July 1992 • Annals of Internal Medicine • Volume 117 • Number 2 



332 



CORRESPONDENCE 



PYRROLIZIDINE POISONING 
To the Editor: 

We have read with interest the 
letter of Ridker and McDermott 
(Am J Med 1989; 87: 701) on the 
hepatotoxicity of herbal teas 
made from comfrey. However, we 
disagree strongly with their con- 
clusion that a diagnosis of pyrro- 
lidine poisoning can be made 
without chemical confirmation. 



Such a practice would return us 
to the situation of dangerous con- 
fusion that has so often sur- 
rounded the question of herbal 
safety. 

Pyrrolizidine alkaloids are 
among the most widespread of 
secondary metabolites developed 
by plants for defense against her- 
bivores; pyrrolizidine alkaloids 
have been estimated to be pre- 
sent in about 3% of flowering 
plant species [1]. The approxi- 
mately 200 known pyrrolizidine 
alkaloids exhibit a wide variety of 
structures and toxicities [2]. 

However, even if one limits the 
question to comfrey (Symphy- 
tum species), four major objec- 
tions to the Ridker-McDermott 
suggestion can be made. 

First, several plant species and 
varieties of Symphytum are in- 
volved in the comfrey trade. A re- 
cent Canadian study [3] that ex- 
amined 13 commercial comfrey 
products revealed the unreliabili- 
ty of commercial labeling of herb- 
al products. Although all prod- 
ucts were labeled either simply 
"comfrey" or "comfrey/Symp/ty- 
tum officinale," six were shown 
not to be S. officinale (common 
comfrey) because they contained 
the pyrrolizidine alkaloid echimi- 
dine, indicative of Symphytum 
asperum and its hybrids, such as 
Symphytum x uplandicum (Rus- 
sian comfrey); Russian comfrey 
has long been recognized to be 
the most common commercial 
comfrey in Britain [4]. In view of 
differing alkaloidal profiles and 
different pyrrolizidine alkaloid 
toxicities, a simple "comfrey" la- 
bel is obviously not a sufficient 
indication of toxic potential. 

Second, the poor quality con- 
trol in the herbal industry fre- 
quently leads to adulteration of 
plant products. Poisonings have 
occurred as a result of consump- 
tion of deadly nightshade 
(Atropa belladonna) sold com- 
mercially as comfrey [5,6]. 

Third, with herbal products 



containing chopped or powdered 
roots, leaves, and herbage, or 
mixtures of substances, botanical 
identification is nearly impossi- 
ble. This situation holds, for ex- 
ample, with the commonly used 
comfrey-pepsin capsules, which 
probably present the highest cur- 
rent risk of pyrrolizidine poison- 
ing in the United States. 

Fourth, even within a defined 
botanical species, there is marked 
variation in alkaloid content, de- 
pending on the time of year the 
material was collected, the loca- 
tion, the conditions of growth, 
maturity, and the part of the 
plant used. Thus, with S. officin- 
ale (common comfrey), there is 
an up to 10-fold greater level of 
alkaloid content in root as com- 
pared to leaf [7], while young 
leaves of S. x uplandicum (Rus- 
sian comfrey) may contain up to 
15 times more alkaloid than old 
leaves [8]. 

In general, herbal poisonings 
tend to be poorly documented. 
There is a requirement for better 
documentation, which would in- 
clude proper identification of the 
toxic material, and chemical 
measurement of the toxin, so that 
the quantity of chemical ingested 
may be appropriately estimated. 
The literature on pyrrolizidine 
poisoning is replete with inaccu- 
rate, scanty reports, as indicated 
in two recent reviews of the area 
[9,10]. Botanical names and herb- 
al names rarely stand in a one-to- 
one correspondence, and the bo- 
tanical identifications that may 
be associated with commercially 
available herbs are frequently in- 
accurate. 

RYA.Sj. HV.XTABLE, Ph.D. 

College of Medicine 

University of Arizona 

Tucson, Arizona 

DE.WIS V.C. AWANG, Ph.D. 

Bureau of Drug Research 

Health and Welfare Canada 

Banting Research Centre 

Ottawa, Ontario, Canada 

1. Smith LW. Culvenor CCJ Plant sources ol hepa- 
totoxic pyrrolizidine alkaloids J Nat Prod 1981. 44 
129-52. 



October 1990 The American Journal of Medicine Volume 89 547 



333 



Toxicants 

of 
Plant Origin 



Volume I 
Alkaloids 



Editor 

Peter R. Cheeke 

Professor of Comparative Nutrition 

Department of Animal Science 

Oregon State University 

Corvailis, Oregon 




CRC Press, Inc. 
Boca Raton, Florida 



334 

42 Toxicants of Plant Origin 

I. INTRODUCTION 

Compared to other groups of naturally occurring toxins, the pyrrolizidine alkaloids (PAs) 
are understudied. There is a relative paucity of information concerning the health conse- 
quences of exposure to humans, but the scope and nature of this problem should not be 
underestimated. About 3% of the flowering plants of the world are estimated to contain 
toxic PAs. The distribution of the alkaloids has been reviewed. 13 Some 160 esterified 
alkaloids are known, and the number is increasing yearly. 1 These alkaloids are scattered in 
332 species and distributed through 63 genera and 13 families. 4 A complicating factor is 
that often these alkaloids are present as, or coexistent with, their corresponding N-oxides. 
With certain exceptions, these neutral substances are almost as toxic as their eponymous 
alkaloids. 56 In 1968, only 105 total alkaloids, esters and nonesters, were listed in the 
monograph of Bull et al. 7 As this century winds down, PAs are probably the most significant 
group of natural products in terms of their adverse effects on humans and their economic 
activities. 

Pyrrolizidine intoxications occur because plants containing them are consumed in food or 
as medicinal herbs (Table 1). Exposure through food may be either because the plant is 
intentionally consumed, as in the use of Symphytum or Petasites as green vegetables, or 
because of contamination of food grains with seeds of pyrrolizidine-containing plants. This 
was the case with the Heliotropium poisoning epidemic in Afghanistan, Crotalaria poisoning 
in India, and Senecio poisoning in South Africa. 

It is easier to suspect PA poisoning than it is to prove it. The patient may have taken a 
variety of herbs, all known by noninformative names, samples of food and herbs may not 
be available for botanical or chemical analysis, and the clinical picture may be ambiguous. 
If a middle-aged person has cirrhosis, is this a long-delayed response to pyrrolizidine in- 
toxication or a consequence of overindulgence in alcohol? To verify a diagnosis of pyrrol- 
izidine poisoning, it is necessary to 

1. Find liver symptoms indicative of pyrrolizidine poisoning. 

2. Show pathognomic changes in liver architecture. 

3. Analyze suspected foodstuffs or herbs the patient had been taking to demonstrate the 
presence of PAs. 

4. Calculate the quantity of alkaloid probably ingested. 

Analysis of samples must be stressed. Even commercially available materials are often 
botanical ly mislabeled. Herbs and herbal preparations are typically in a form unsuited for 
botanical identification. Most botanists can do little with preparations that are chopped, 
macerated, blended, mixed, or powdered, or which contain only roots. Examples of prep- 
arations I have been asked to examine are shown on Figures 1 to 3. The patients who had 
taken the one gordolobo sample and the te mar died. Microscopic examination of the te mar 
sample permitted its tentative identification as a Crown species. Matarique is usually listed 
as being Cacalia decomposita, a pyrrolizidine-containing species. 8 However, it would take 
a brave botanist to confirm that identification from the sample given. Indeed, recent field 
collections indicate that most matarique sold in Mexico may in fact be Psacalium rather 
than Cacalia. 910 

One reason that PAs are not taken more seriously as health hazards is the lack of reliable 
data as to the frequency of poisoning, and the difficulty of obtaining such data. Heavy 
outbreaks of acute poisoning occur in areas of the world remote from the West, such as 
central Asia. Chronic poisoning has been found in subcultures operating outside the frame- 
work of traditional Western medicine. Increased risk of exposure applies as much to the 
large numbers of Americans who patronize health food stores as it does to the Hispanic and 
Indian cultures of our nation with their curanderos, herbalistas, and medicinal plants. 8 - 9 " 12 



335 



44 Toxicants of Plant Origin 




FIGURE 1. The guessing game: these roots were purchased in Mexico under the name "matanque" by an 
American who took extracts of them regularly as a kidney prophylactic. What plant do they come from? (Photo 
by R. J. Huxtable.) 




FIGURE 2. Death in a tea cup: these chopped leaves and twiglets were sold as a herbal tea under the name 'te 
mar". A middle-aged woman drank 1 gal of this tea a day for 3 d. lapsed into a coma, and died (Photo by R. J 
Huxtable.) 



336 



46 



Toxicants of Plant Origin 



Complete 
recovery (48%) 



Clinical 
recovery (20%) 



'Latent period oi years 



Acute veno-occlusive 
disease 
(sudden hepatomegaly 
and ascites) 



(13%) 



Subacute veno - occlusive 

disease 

(persistent firm hepatomegaly) 



Chronic veno-occlusive 

disease 
(cirrhosis 01 liver) 



Rapid death (19%) 
(increasing iaundice 
cholaemia) 



Clinical improvement 



Complete recovery 



FIGURE 4. The three stages of veno-occlusive disease. (Redrawn from Stuart, K. L. and Bras, G., Q. J. Med., 
26. 103. 1957.) 

theless. A woman suffered from excessive menstrual bleeding following a triad of behaviors 
almost classic for herbal poisonings: the poisoned person used a large number of herbs 
(about 40) supplemented with numerous food additives and ethical drugs; she took large 
amounts of herbs; and she had persisted with the regimen for many years. 19 

H. THE TOXIC ACTIONS OF PYRROLIZIDIMES 



A. Veno-Occlusive Disease of the Liver 

The reported cases of pyrrolizidine poisoning are listed in Table 1 . Typically, cases which 
have come to attention have involved liver damage or, more specifically, veno-occlusive 
disease. Veno-occlusive disease is a highly characteristic finding which can be considered 
pathognomonic of PA poisoning. It occasionally occurs as a consequence of chemotherapy 
with drugs such as cytarabine, but apart from this, no other cause is known. Veno-occlusive 
was first recognized and named as a clinical entity in the West Indies 20 and was fully and 
clearly described. 21 

It is a disease of the small branches of the hepatic veins. These become occluded, leading 
to ascites, edema, and reduced urinary output. It carries a high mortality, and if survived 
leads to cirrhosis. Children are more vulnerable than adults. Various clinical descriptions 
have appeared. 22 ' 26 The clinical course given by Stuart and Bras 21 is still a good overview 
(Figure 4). 

The disease can be clinically divided into three stages: the acute, the subacute, and the 
chronic. The acute phase involves hepatomegaly and ascites. This phase may be of short 
duration, either resolving or progressing to the subacute stage. This involves persistent firm 
hepatomegaly with recurrent ascites. The chronic phase consists of cirrhosis and liver failure. 

Histologically, veno-occlusive disease is associated with occlusion of the smaller branches 
of the hepatic vein, due to endothelial proliferation and medial hypertrophy. Occlusion leads 
to centrilobular congestion which, in rum, results in widening of the sinusoids and pooling 
of blood. This finally leads to necrosis of surrounding liver tissue and replacement fibrosis. 
The final stage is centrilobular cirrhosis. 

The involvement of the smaller hepatic veins differentiates veno-occlusive disease from 
the Budd-Chiari syndrome. This is associated with thrombi formation and occlusion of the 



337 



48 Toxicants of Plant Origin 




FIGURE 5B. 

a response to the increased vascular resistance in the pulmonary circulation. The hypertrophy 
is associated with an increase in the percent of collagen in the tissue, in contradistinction 
to the pulmonary hyperplasia which is also a feature of pyrrolizidine-induced cardiopul- 
monary toxicity. 29 

Experimental pulmonary hypertension has been produced in rats 2830 and primates. 31 We 
were unable to produce unilateral ventricular hypertrophy in rabbits. 32 

Pyrrolizidine-induced pulmonary arterial hypertension is a delayed response. The disease, 
and the consequential right ventricular hypertrophy leading to cor pulmonale, is clinically 
"silent" until it reaches an advanced stage and is hard to diagnose without right heart 
catheterization. It is perhaps, therefore, not surprising that only one case has been unequi- 
vocally attributed to PA poisoning. There may be a delay of years between initial exposure 
to PAs and the diagnosis of pulmonary arterial hypertension, and clinicians are insufficiently 
sensitized as to the possibilities of a toxic origin. 

Although only one case of pulmonary hypertension has been ascribed to pyrrolizidine 
poisoning in humans, 33 pulmonary involvement was a common observation in pyrrolizidine 
poisoning in the West Indies. It included pleural effusions 21 and fine mottling which was 
apparent on X-rays. 34 Two pyrrolizidine-intoxicated patients died of bronchopneumonia. 
Pleural effusions following pyrrolizidine exposure have also been reported from England 18 
and the U.S. 35 - 36 



C. Other Organ Systems 

A wide species variation is seen in organs typically involved in pyrrolizidine toxicity. 
The response in horses is primarily neurological, in sheep hemolytic, in cattle gastrointestinal, 
in pigs and dogs hepatic, and in chickens and turkeys pulmonary, muscular, and hepatic. 

Involvement of the central nervous system (CNS) occurs commonly in horses following 
exposure to pyrrolizidines, and is reflected in some of the names coined for such exposure 



338 



50 Toxicants of Plant Origin 

Pyrrole metabolites of pyrrolizidines, produced in the liver, are bidentate alkylating agents. 
These substances cross-link cell macromolecules, such as RNA, DNA, and proteins. 53 This 
may be the basis of their carcinogenic and mutagenic activity. 

m. PYRROLIZIDINE POISONING OF HUMANS 

A. Crotalaria (Leguminosae) 

Crotalaria is a genus of several hundred known species which are widespread in tropical 
and subtropical regions. There are over 300 in Africa alone. Some 53 species have been 
shown to contain hepatotoxic pyrrolizidines, and some 12 species have pyrrolizidines of the 
nonhepatotoxic type. The genus name derives from the Greek krotalus, or rattle, this referring 
to the characteristic seed pods of this genus. Crotalaria tend to be rank plants, typically 
with yellow flowers. The leaves are palmate or undivided. From some Indian species, a 
high quality fiber has been woven, but in general, this genus has few economic or horticultural 
uses. 

C. spectabilis has spread from its homeland in central and southern India and is now well 
established in the southeastern U.S. This large, distinguished plant was first planted in 
Florida in the 1920s as a cover crop for fallow fields, but wandered from supervision into 
hedgerows and meadows throughout the old south. Another toxicologically significant plant 
is also a wanderer. C.fulva is native to India, Sri Lanka, and Indonesia, but is now established 
throughout the Caribbean. 

1. Toxicology 

Typical Crotalaria alkaloids are macrocyclic diesters containing 1 1 atoms in the macro- 
cyclic ring. Monocrotaline and fulvine have been implicated in human poisonings (Figure 
6). 

What later came to be recognized as pyrrolizidine poisoning was known in stock animals 
as long ago as 1860, caused largely by Senecio and Crotalaria species. Some of the names 
by which pyrrolizidine poisoning was known in various parts of the world have been listed 
by Huxtable. 37 

Monocrotaline and fulvine have been among the most intensively investigated pyrrolizi- 
dines. Apart from their hepatotoxicity, these alkaloids are also pneumo- and cardiotoxic. 
The seeds of C. spectabilis have been used to produce such damage in laboratory ani- 
mals. 5 *" 5 * In fact, C. spectabilis has been termed the "pulmonary hypertension plant". 57 

Pneumotoxicity is exhibited by fulvine 58 * 61 and monocrotaline. 28 - 30 - 62 " 64 Pulmonary arterial 
hypertension and right ventricular hypertrophy are readily produced with monocrotaline in 
rats, mice, and nonhuman primates, although we were unable to produce such conditions 
in rabbits. 32 

2. Human Exposure 

Some of the numerous folk usages of this genus have been listed by Mattocks. 1 C. fulva, 
C. incana, and C. longirostrata have wide employment in the Caribbean countries. 69 It has 
been suggested that one reason for the high incidence of veno-occlusive disease among 
babies in Jamaica is exposure of the infants to alkaloids in their mother's milk. 66 However, 
along the Mexican- American border, it is common for even newborn babies to be given 
various herbal teas for various reasons, and it is to be imagined that the same pattern might 
have held in Jamaica. With the fall in home deliveries, the habit must be decreasing. 

Watt and Breyer-Brandwijk 67 list many usages for the numerous African Crotalaria. They 
quote older literature that C. junca was used as a vegetable in the West Indies, and also 
that the seeds were eaten. C. retusa is taken as a vegetable in Tanganyika, while both leaves 
and roots are reportedly consumed in India and West Africa. The seeds of C. mucronata 



339 



52 Toxicants of Plxint Origin 




FIGURE 7 . Ascites associated with veno-occlusive disease in the West Indies in infants 5 and 7 years 
old. (From Bras. G.. mThe Liver. Gall, E. A. and Mostofi, T. K... Eds.. Williams &. Wilkins, Baltimore, 
1973, 406. With permission.) 



workers 34 - 74 150 cases. Bras et al. 75 were the first to recognize the distinctive morphological 
features of hepatic centrilobular necrosis with occlusion of the smaller hepatic veins, and 
they gave the condition the name by which it is now known. The condition was carefully 
differentiated from Jamaican vomiting sickness, another liver disease affecting primarily 
young children in which gluconeogenesis is impaired and blood sugar levels fall to zero. 76 
This condition is now known to be caused by the consumption of the unnpe ackee fruit, 
from the tree Blighia sapida. Veno-occlusive disease was also differentiated from alcoholic 
cirrhosis, parasitic disease, and protein malnutrition (kwashiorkor). 77 The Jamaican workers, 
in a careful analysis, differentiated three stages of the disease, the acute, the subacute, and 
the chronic (Figure 4). 2 ' This description has stood the test of time and is still a useful 
codification of the stages of hepatic damage caused by pyrrolizidines. 

The chronic occurrence of veno-occlusive disease in the West Indies in both children 21 - 23 - 78 
and adults 24 has been stressed by a number of authors. Stuart and Bras 24 report in detail 10 
adult cases of whom five died, and provide information on a further 84 cases. Of 1560 serial 
autopsies, 4.9% showed cirrhosis.' 7 It is sobering to read that 28.5% of these autopsies were 
on children less than 1 year old. 

Bras et al. 75 considered the disease was possibly associated with the use of Senecio- 
containing teas. However, in follow-up papers, 79 *° they concluded veno-occlusive disease 
in Jamaica was caused by ingestion of Croialana species. C.fulva in particular, a conclusion 



340 



54 



Toxicants of P lam Origin 






■JL .--»- .- -T 'V-'^Tr^aA.-^r i^-rv— - ■ - * 77--.* • -■» - 




FIGURE 9. Veno-occlusive disease in India, caused by Crotalaria contamination of food grain. (From Krish- 
namachari. K. A. V. R., Bhat, R. V., Krishnamurthi, D., Krishnaswamy, K., and Nagarajan, V., Indian J. Med. 
Res.. 65. 672, 1977. With permission.) 

For example, in a typical case reported by Hill et al., 34 a 10- month-old male was fed 
only on Quaker® oats plus very dilute condensed milk, with breast milk at night. The 
Quaker® oats amounted to half a pound per week, shared with two other children! At 2 
weeks before admission with veno-occlusive disease, he had been violently poisoned by 
castor oil seeds (Ricinus communis, containing the protein ricin, one of the most toxic 
substances known). One is pleased to read that when offered milk, meat, and eggs in hospital, 
the young patient ate ravenously. 

The incidence of veno-occlusive disease has fallen in Jamaica in recent years due to a 
strenuous information and public health campaign. 

Deaths from pyrrolidine poisoning have also been reported from Barbados, where young 
children were given teas prepared from C. retusa as a "treatment" for whooping cough. 79 

Although Crotalaria alkaloids are widely used to produce cardiopulmonary disease in 
experimental animals, only one clinical report of Crora/aria-induced pulmonary hypertension 
has appeared." This, one suspects, is due more to the difficulties of diagnosis and attribution 
as to cause than to a true low incidence. A Tanzanian patient died with primary pulmonary 
hypertension. The patient came from an area where many species of Crotalaria grow, 
including C. laburnoides. The seeds of this plant produce cardiopulmonary disease when 
fed to rats. However, the authors were unable to show that the patient, a male of 19 years, 
had taken any herbs containing Crotalaria. 

Epidemics of Crotalaria poisoning have occurred in India as a result of grain contami- 
nation. Two outbreaks occurred in Mahya Pradesh in 1973 and 1975. 83fM In certain villages 
in the affected area, veno-occlusive disease was endemic (Figure 9). Of 67 cases that were 
studied, 28 died. Mycotoxins were excluded as a cause. Millet, known locally as gondii, 
the common grain of the area, was found to be contaminated with the seeds and pods of a 
Crotalaria species (Figure 10A and B) subsequently identified as C. nana, a pyrrolizidine- 
containing species. 85 86 The pods are larger than millet seeds, while the Crotalaria seeds 



341 



56 



Toxicants of Plant Origin 




FIGURE 11. The seeds of Crotalaria spectabilis. (Photo by R. J. Humble.) 



expressed by open pods are smaller. The similarity of the kidney-shaped seeds to those of 
C. spectabilis is obvious (Figure II). Alkaloids were isolated from the contaminated grain 
and shown to be chromatographically identical with monocrotaline and fulvine (Figure 6). 
The seeds contained 0.53% alkaloids. Contamination was up to 2% weight by weight of 
seeds. 

Outbreaks tended to be seasonal, cases concentrating into the late fall. When 3 villages 
were re-examined in 1976 (i.e., the year after the epidemic), 35 cases of endemic ascites 
were found in a population of 1019. In one village, 9% of the population was affected. The 
episodic nature of exposure was a feature of this outbreak. When food samples were collected 
on two occasions for analysis, poor correlation was found between alkaloid content and the 
presence of veno-occlusive disease in the house. Thus, some houses with high contamination 
were free of disease, and vice versa. However, it is probable that the sampling is not truly 
representative and that the degree of contamination is highly variable. A family might be 
eating heavily contaminated grain one week, and clean grain the next. 

Assuming 2% seed contamination of the grain, the authors calculated a maximum daily 
intake of 40 mg of alkaloid. However, the actual average daily intake must have been much 
lower. It would have been useful if the average level of contamination of the grain in an 
affected village could have been determined on one occasion, and this value used to calculate 
average exposure. 

Veno-occlusive disease was reported in a 35-year-old woman in Missouri, a native Ec- 
uadoran who had obtained a herbal tea from a "herbologist" (sic) in Quito. 13 She drank 2 
1 of tea a day for 6 weeks, and 1 1/d thereafter. The tea supposedly contained C. juncea, 
although unfortunately the authors do not give their authority for this statement. Whatever 
the source of the alkaloid, this case is the first report of human veno-occlusive disease in 
the U.S. although probably not its first occurrence. 



342 



58 



Toxicants oj Plant Urigin 



Table 2 
PYRROLIZIDINE ALKALOIDS IN SYMPHYTUM* 

Alkaloids + N oxides (% dry weight) 





Fresh 


Dried 






Comfrey sample 


leaves 


leaves 


Roots 


Ref. 


5. asperum 


0.009 


0.059 


__ 


22 


S. officinale 


0.006 


0.062 


— 




S. x uplandlcum 


0.009 


0.09 


— 




Various 


— 


0.013—0.062 


— 


98 


Tea 


— 


0.009—0.03 


— 




5. x uplandlcum 


— 


0.22 (y) 


— 


92 




— 


0.05 (m) 


— 




S. x uplandlcum 


0.15 (y) 


— 


— 


91 




0.05 (int) 


— 


— 






0.01 (m) 


— 


— 




Commercial 


— 


(0.005)" 


0.14—0.37 


93 


5. asperum 


0.01 


— 


— 




5. officinale 


— 


— 


0.07 


102 



' y, young leaves; int, intermediate; m, mature leaves. 
* Undetectable. 

Adapted from Mattocks. A. R., Chemistry and Toxicology of Pyrrolidine 
Alkaloids. Academic Press, London, 1986. 270. 



These alkaloids are all of the hepatotoxic structural type. 88 Symphytum has been shown 
to be carcinogenic to rats, the roots being more so than the leaves. 94 Liver and bladder 
tumors were produced. Studies with individual alkaloids have shown carcinogenicity for 
lasiocarpine 95 and symphytine. 96 

2. Human Exposure 

Despite the relatively small number of alkaloids and the paucity of established cases of 
poisoning, Symphytum is of major concern in the industrialized nations because of the 
widespread use of 5. officinale (common comfrey) and its hybrids as a vegetable, herb, and 
food supplement. Russian comfrey (S. unplandicum) is widely cultivated in England and 
Australia. 97 Other widely used species include S. uplandlcum and S. asperum. They are 
cultivated in many countries and present in many products. 88 9l94 - 98 " Comfrey can be found 
in skin creams, bath oils, eye lotions, ointments, hair products, and skin conditioners. 100101 
The ability of Symphytum alkaloids to be absorbed through the skin may have some relevance 
to human exposure. 102 

A manufactured drug with the equivalent carcinogenicity of comfrey would not be per- 
mitted to be marketed in the U.S., but because it is a natural product and not a food additive 
in the regulatory sense, there are no current limitations on its sale. 

The use of Symphytum is ancient, it being known to the Greeks and Romans. The species 
name, officinale, indicates its place in medieval herbals. Typical of such plants, the claims 
made for it are those of a panacea, or cure-all. Some of these myriad claims are listed by 
Duke 103 and Bianchini et al. 104 A quote from an 18th-century herbalist will give the flavor 
of expectations surrounding this coarse and hairy plant:' 05 

The great Comfry helpeth those that spit Blood, or make a bloody Unne. The Root boiled in Water or Wine, and 
the Decoction drunk, helpeth all inward hurts, bruises and wounds, and Ulcers of the Lungs, causing the flegm 
that oppressed! them to be early spit forth: its stayeth the defluxions of Rheum from the Head upon the Lungs. 
the fluxes of Blood or humors by the Belly. Womens immoderate Courses, as well as the Reds and the Whites, 



343 



60 



Toxicants of Plant Origin 




FIGURE 13. Free enterprise: a sample of comfrey-containing capsules and tablets obtained from a single health 
food store. (Photo by R. J. Huxtable.) 

she had taken a leaf preparation, although no information was given on the container. It 
was calculated that over a period of 6 months she had consumed a minimum of 85 mg of 
PAs. This patient was typical of poisoning cases which have come to my attention in terms 
of the extent and variety of her use of herbs and other "food additives". These included 
daily supplements of vitamins C, K, E, and B complex, plus lecithin, stereotrophic adrenal 
bovine extract, and salts of calcium, magnesium, potassium, zinc, and iron, chamomile tea, 
plus a tea called MU-16 prepared, according to the packet, from a complex mixture of 
plants. This tea, manufactured in Japan, was distributed by a company called Erewhon. One 
does not need to be a crossword fanatic to solve the anagram. It contained low levels of 
Symphytum alkaloids. 110 

The patient was released following performance of a portacaval shunt. She was subse- 
quently readmitted with transient encephalopathy following the consumption of in excess of 
200 g protein in a 12-h period. 

An unreported case involved an elderly woman admitted to hospital with veno-occlusive 
disease and severe portal hypertension progressing to cirrhosis. 111 She had a long history of 
herbal use, regularly taking some several dozen preparations. For at least the 6 months prior 
to admission, she had taken six capsules per day of a comfrey-pepsin preparation containing 
321 mg/kg of free alkaloids and 667 mg/kg of /V-oxides. I thank Drs. Liithy and Zweifel 
for the mass spectrometric and chromatographic analysis of this sample. The woman had 
also taken a "fenucomf ' preparation purportedly containing comfrey. However, only traces 
of alkaloid were found in this preparation (4.4 mg/kg). It can be calculated that over the 6 
months prior to admission, the woman had consumed 512 mg of PAs. 

A further unpublished case that may or may not represent Symphytum poisoning occurred 
in New Orleans. 112 A middle-aged woman, an herbalist, drank 48 oz of comfrey tea prepared 
from 8-10 large leaves daily for 3 months. In addition, she consumed new shoots of confrey 



344 



62 



Toxicants of Plant Origin 



R 1 



CH,OR 2 




R 1 v ,Me 



CH 



Me 



R 2 -C — C— OH 
I I 
Me C0 2 H 



C=C 
Me' N CO,H 



Angelic 





R' 


R 1 




A. Alkaloids 




7-Angeloylheliotridine 

Heliotnne 

lndicinc 

Acetylindicine 

Lasiocarpine 

Echinatine 


Angeloyl 

H 

H 

H 

Angeloyl 

H 


H 

Heliotroyl 

Trachelanthoyl 

AcetyltrachelanthoyI 

Lasiocarpoyl 
Viridifloryl 


Supinioe 
Heleurine 


— 


Trachelanthoyl 
Heliotroyl 



B. Esterifying Acids 



Heliotnc 


Me 


H 


Lasiocarpic 


Me 


OH 


Trachelanthic* 


H 


H 


Viridifloric* 


H 


H 


Echinudinic 


H 


OH 



These acids are stereoisomeric at the indicated position. 



FIGURE 14. PAs in Heliovropium implicated in human intoxications. H. lasiocarpum 
contains heliotnne and lasiocarpine; H popovii heliotnne; H eichwatdii heliotnne. lasio- 
carpine, and 7-angeloylheliothdine; and H. indicum indione. acetylindicine, indicimne, 
echinatine, supinine, heleunne, lasiocarpine. and heliotnne. The alkaloids in H. angiosper- 
mum appear not to have been charactenzed. Supinine and heleunne lack the 7-hydroxy group, 
lndicinine is an uncharactenzed ester of retronecine. 



345 



64 Toxicants of Plant Origin 



MeXH 



0^\ 




FIGURE 15. PAs in Trichodesma incaman implicated in human intox- 
ications. Trichodesmine, R = OH; incanine, R = H. 

produced death in all animals within 2 to 6 h, as a result of respiratory depression. Higher 
doses produce immediate death. 

Trichodesma incanum has caused significant livestock losses in central Asia. This perennial 
spreads by rhizomes and normally grows on arid hillsides. However, it also infiltrates crops. 
In horses, consumption of Trichodesma produces a disease known locally as "suiljuk". The 
principal findings are proliferative changes in the lungs, particularly in perivascular con- 
nective tissue. 136137 Degenerative changes are also seen in liver, kidneys, and heart. 

In cows, the primary organs involved are the heart and liver, 138 the animals dying of a 
"cardiodystrophy". Pneumonia is also seen. 

Trichodesma alkaloids differ from the Crotalaria alkaloids only in the presence of an 
isopropyl group in place of a methyl group alpha to an ester function. It is possible that the 
isopropyl group increases steric hindrance for hydrolysis of the ester group, permitting pyrrole 
metabolites to survive longer in the circulation and to reach the brain. 

2. Human Exposure 

T. africana is used as a medicinal herb in Asia. 139 

3. Human Poisoning 

An outbreak of Trichodesma occurred in the Samarkand region Uzebekistan in 1950. "° 
This outbreak differed from the Heliotropium outbreaks occurring earlier in the same area 
in that the primary symptomatology was extrahepatic. Over 200 patients were affected 
following the consumption of bread prepared from grain contaminated with the seeds of 
Trichodesma incanum. The so-called "bitter bread" contained up to 3% alkaloids. An odd 
feature of this outbreak was that children below the age of 10 were not affected, nor were 
breastfed infants of affected mothers. Exposures were acute. Following exposure, there was 
a latent period of 10 d, then vertigo and recurring headaches developed, leading to nausea 
and vomiting. This was followed by a generalized malaise which progressed to delirium, 
loss of consciousness, and death from respiratory depression. At least 44 people died. 

E. Senecio (Compositae) 

The Senecio are a numerous and varied genus in the Compositae. There are some 1500 
species worldwide, making them one of the largest genus in the angiosperms. They vary 
from weeds such as S. jacobaea and garden ornamentals such as S. cineraria ("dusty miller") 



346 



66 Toxicants of Plant Origin 

whom died. 14 The dead child consumed around 65 mg over a 4-d period, and the other 
child, 70 to 140 mg over a 2- week period. 

Among the Senecio, S. vulgaris, or common groundsel, has a long history of herbal use. 
Bianchini and Corbetta 104 list the usual virtures of the plant, but then point out that as it 
contains senecionine it is toxic. They give a warning, "it should only be given under proper 
medical supervision" ! S. aureus is another supposed panacea among the Senecio. The claims 
made for this plant would fill several pages. S. longilobus, responsible for the Arizona 
poisonings, 33 - 36 is widely used by various ethnic groups in the southwestern U.S. Thus, it 
is recorded as being "used extensively in the domestic medicine of the indians," 148 and 
Moerman 149 records it as in use among the Navajo and Hopi. In addition, other Senecio 
species are used by Navajos, Zunis, and Aleuts. 149 Various Senecio species are listed by 
Ford 8 as being sold by herbalists in Mexico. 

Senecio alkaloids are known to be excreted in the milk of animals fed or grazed on 5. 
jacobaea and to be found in honey from bees foraging on the same plant. There is a 
possibility, therefore, that dairy products, meat, and honey for human consumption could 
be contaminated with Senecio alkaloids. No thorough investigation has been carried out on 
this problem, and so the scope and level of contamination remain unknown. Whether or not 
any health risk is posed by this route of pyrrolizidine exposure must await further research. 

Given the toxicity of PAs, it was surprising to find a pyrrolizidine-containing product in 
the Physician's Desk Reference (Figure 17): '"Succus cineraria maritima' is an extract of 
S. cineraria marketed for local application to the eye as a safe lymphagogue, to increase 
circulation in the intraocular tissues and normal metabolism, functions so necessary from 
the standpoint of the normal physiology of the eye." It is claimed that use of the material 
can check or even abort opacities of the eye. This insert has presumably been approved by 
the FDA. This prescription drug contains senecine and senecionine (Figure 16). A justifi- 
cation for its use? "It gives comfort to the patient," the insert continues, "to know that 
something potentially beneficial is being done." This product has been removed from the 
1987 Physician's Desk Reference. 

It is of interest to note that Morton 65 records the juice of 5. cineraria being used herbally 
in Venezuela to treat sore eyes and lists various references for this folk use. She also records 
the use of 5. cancellatus in Haiti for a related purpose. There, the plant is fried in milk or 
butter and applied in a cloth to the eye. Furthermore, Bennett and Zingg refer to the Zuni 
use of the blossoms of S. multicapitatus. The blossoms are infused in water which is then 
squeezed onto the eyes to relieve inflammation. 130 

3. Human Poisoning 

The first documentation of pyrrolizidine poisoning in humans came from South Africa, 
in 1920. 15 ' This outbreak was caused by the consumption of bread contaminated with seeds 
of S. ilifolius and S. burchelli. Stomach pains on eating progressed to hepatomegaly and 
ascites. These authors report the period from onset to death ranged from 10 d to 2 years. 
Most of those affected were children, but in a number of cases whole families were involved. 
This familial pattern is characteristic of grain contamination, being seen with the Heliotro- 
pium and Trichodesma outbreaks from central Asia and the Crotalaria epidemics in India. 

A highly significant observation of Willmot and Robertson 131 was that disease characteristic 
of Senecio poisoning had been known in the area for at least 10 years before their enquiries, 
but the etiology had never been investigated. Their own work on this subject was curtailed 
by the influenza epidemic which swept the world in the wake of the Great War. 

Some 30 years later, a further report appeared from South Africa of poisonings due to 
Senecio contamination of grain. 132 Twelve cases of Chiari's syndrome were investigated; 7 
of the patients died following treatment. Those affected came from a district in which the 
disease was well-known, another indication of the severe underreporting of pyrrolizidine 



347 



68 



Toxicants of Plant Origin 




FIGURE 18. A fine specimen of Senecw longilobus. growing in Gardner Canyon, southern Arizona. (Photo by 
R. J. Huxtable.) 



epidemic was due to pyrrolizidine poisoning, in no individual case were the criteria outlined 
in the introduction followed. Actual herbs being used by an affected family were not obtained, 
and no specific analysis for the class of alkaloid was performed. Details of these outbreaks 
have been given under Crotalaria, above. 

Nine cases of veno-occlusive disease, suspected to be caused by Senecio contamination 
of food grains, were reported in 1970 from Iraq. 1 " All the patients were Bedouin children 
from three families in whom the disease appeared suddenly. This suggests an acute poisoning. 
These families shared their food and came from a region known to be contaminated with 
Senecio, hence the authors' suspicions. 

In the 1970s, a number of cases of liver disease were reported from the southwest U.S. 
caused by consumption of herbal teas prepared from Senecio longilobus (Figure 18).' 4 - 35 - 36 
The tea was sold under the herbal name gordolobo yerba. A 6-month-old girl, fed the tea 
over a 2-week period, developed veno-occlusive disease and ascites (Figure 19). The acute 
stage was survived (Figure 20), and the patient developed cirrhosis (Figure 21). 3S Analysis 
of the tea revealed an alkaloid content of 1.3%, 1% of which was in the form of N-oxides. 154 
Of the four alkaloids present, the major one was retrorsine A/-oxide. IS4 In the majority of 
reported poisoning cases, only rough estimates are available as to total exposure. In this 
case, it was determined that the patient had consumed an amount of tea equivalent to 147 
mg alkaloid. However, when tea was prepared in the laboratory according to the mother's 
procedure, slightly over half the alkaloids were not extracted. Thus, it could be calculated 
that the patient had consumed 70 mg of a retrorsine A/-oxide-rich mixture of pyrrolizidines 
over the 2 weeks. 

A related case involved the death of a 2-month-old male following administration of 
gordolobo for 4 d. 36 In this case, the herb was obtained not from a herbalist, but a pharmacist 
who "dispensed" it in a popcorn bag (Figure 22). 

Four other cases, including two deaths, of young children developing liver disease after 



348 



70 



Toxicants of Plant Origin 




FIGURE 21. The ulrrastrucrure of the chronic stage of veno-occlusive disease. A liver biopsy taken 2 months 
after admission from the patient shown in Figure 19 reveals cirrhotic changes typical of the chronic stage of the 
disease Collagen fibnls can be seen near the upper left. 




FIGURE 22. The deadly clown this sample of gordolobo verba (Senecio longilobusi. sold by a licensed phar- 
macist, killed a 9-week-old child (Phoio bv R J Huxtable.) 



349 



72 



Toxicants of Plant Origin 



Table 3 

PYRROLIZIDINE POISONING OF 

UNKNOWN SOURCE 



Counlr\ 



Exposure 



Ref. 



Germany 




159 


Egypi 




160 


Egypt 


Unknown 


165 


South Afnca 


Herbs 


166 


India 


Herbal medicines 


169 


India 


Grain contamination 


170 


U.K. 


Herbal tea 


18 


U.S. 


Herbal tea 


173 


China 


Herbal medicine 


172 


Israel 


Unknown 


174 



167 



171 




FIGURE 23. Veno-occlusive disease in Egypt of unknown origin. (From Safouh. M. and Shehata. A H., J. 
Pediatr., 67. 415. 1965. With permission.) 

ferences in detail, the syndrome could not be clearly distinguished from the veno-occlusive 
disease found in Jamaica. (3) the age distribution distinguished the Egyptian disease from 
"symptomatic hepatic vein occlusion" (i.e.. Budd-Chian syndrome), and (4) there is a 
likelihood of the condition being caused by Senecio contamination of food supplies. 

Three cases of veno-occlusive disease were reported from South Africa in 1957. I66 All 
patients were under 1 year, and all died. They had been breast-fed. and no history could 
be obtained of herbal usage. The comment is made, however, that "it is common for African 
children to be given witch doctors' medicines, this fact usually being concealed when the 
child is brought to hospital." No thrombi were found in the larger hepatic veins. 

Later, a further nine cases were reported, five being less than 18 months old, and the 
others less than 30 months. 167 One of the children died. Herbs had been given to four of 
the children, but analysis of samples from three families failed to reveal Senecio alkaloids. 
Was there a possibility that the mothers were using pyrrolizidine-containing herbs or con- 
taminated grain, and that the children were exposed via the milk? 

An adult American with veno-occlusive disease was reported by Scott et al. 168 Extensive 



350 



74 Toxicants of Plant Origin 

most common home remedies used by Mexican- Americans. I90191 Eupatorium species are 
widespread in North America. All appear to contain pyrrolizidines, including E. perfolia- 
tum. I92193 The latter, under names such as boneset, feverwort, and others, is an ancient and 
widely used herb and household remedy. 

Why have not more cases of pyrrolizidine poisoning been reported if exposure is so 
extensive 9 A major reason is that it has not been looked for. Knowledge of pyrrolizidine 
toxicity is not widespread among those responsible for health care, and thus an association 
is not made when puzzling, idiopathic liver disease is encountered. Where cases are sus- 
pected, they may not be reported because the association is based on a chain of circumstantial 
evidence, some of the links of which may be weak. As is clearly evident even from extensively 
investigated cases, the move from suspicion to proof may be a difficult one to make. In 
adults receiving chronic low-level exposure in the form of herbs and medicines, the first 
clinical condition to be detected may be cirrhosis, which can be caused by a number of 
conditions, including overindulgence in alcohol. A more disturbing possibility is that sub- 
acute or chronic exposure may result in extrahepatic damage. Based on animal studies, this 
could include cor pulmonale and pulmonary arterial hypertension — conditions hard to 
diagnose, impossible to treat, and difficult to trace as to cause, particularly when the con- 
sequence may be years removed from its occasion. Single doses of monocrotaline in rats 
produces lung disease in addition to cirrhosis. 194 " 196 

Individual susceptibility may also be involved. Two highly significant variables are age 
and sex. Males are more susceptible than females, in keeping with the greater ability of 
males to convert pyrrolizidines to toxic metabolites in the liver. 47197 There is also abundant 
evidence from various experimental species that younger animals are more susceptible than 
older to pyrrolizidine poisoning. Other factors affecting susceptibility to pyrrolizidines in- 
clude synergistic interactions with nutritional state and other ethical or indigenous medicines 
being used. The clinical course of the cases reported by Datta et al. 125 appears to have been 
exacerbated by the use of properly prescribed anticonvulsants. Animal studies show not only 
a sex difference in hepatic metabolism of pyrrolizidines, 47 but a profound increase in met- 
abolic rate and, hence, toxicity after exposure to barbiturates. Many, many agents, like 
barbiturates, induce hepatic metabolism, including social drugs such as alcohol and agri- 
cultural chemicals such as DDT — which is still extensively used in the so-called Third 
World. Pyrrolizidines have been shown to act synergistically with aflatoxin in the production 
of cirrhosis and hepatomas in primates. 198 

Finally, the high variability of the alkaloid content of plants must not be overlooked, nor 
the chemical stability of the alkaloids. 199 Alkaloid content within a species varies from 
individual plant to plant, 200 within a given plant it varies throughout the year, and it also 
varies depending on the plant part. Thus, older Symphytum leaves have a lower concentration 
of alkaloids than do younger leaves (Table 2), and Symphytum roots are an order of magnitude 
richer in pyrrolizidines than are the leaves. Heath et al." found that the toxicity of the 
Crotalaria species they worked with decreased on storage, indicating breakdown of alkaloid. 

It can be concluded that the herbal use of Senecio, Symphytum, and Crotalaria species 
containing pyrrolizidines poses clear and demonstrated risks. Clinical reports have not been 
limited to any one region of the world. Risks are associated with both home-prepared and 
commercially available herbs. Most cases of poisoning to date reflect high acute or chronic 
exposure or exposure of peculiarly susceptible individuals (the young, the malnourished, 
etc.). It can be expected that more intoxications will be detected, possibly at lower total 
exposure levels. There are indications that pyrrolizidine intoxication leading to liver disease 
is more prevalent than the reported case frequency would indicate. Populations are routinely 
being exposed to levels of alkaloids, particularly Symphytum alkaloids, above those at which 
intoxications have been reported. 



351 



76 Toxicants of Plant Origin 

ens flabby uterine ligaments. In addition, it can be used to treat coryza. dropsy, gleet, 
neurasthenia, phthisis, prostatitis, spermatic cord pain, renal colic, puerperal mania, spas- 
matic constipation, liver malfunction, and disturbances of the blood stream due to spasmodic 
character. 107 A similar list is given by Christopher. 214 S. aureus is, in addition, a pectoral, 
a tonic, and a vulnerary. Both authors agree it is useful for leukorrhea, as indeed is comfrey. 
This latter panacea is useful for scrofula, ulceration of the kidneys, female debility, enlarged 
glands, psoas abcess, and the effects of sexual excess. 107 It also is a vulnerary, an alterative 
and a blood purifier, 215 and highly suited for female debility. 214 And much more is claimed 
by these and other authors for these two herbs, selected more or less at random. 

Three characteristics of such claims should be noted, which appear throughout the vast 
herbal literature: 

1. The ancient medical terminology (e.g., phthisis, gravel, gleet). 

2. The emphasis on treatment of symptoms rather than causes (e.g. , leukorrhea, enlarged 
glands). 

3. The use of vague, all -encompassing descriptors (e.g., gynecological disorders, liver 
malfunction, disturbances of the bloodstream). 

These characteristics are indications both of the persistence of herbal lore and of its 
derivation from accepted medical practice in an era when etiologies were uncertain, diseases 
with similar symptoms could not be differentiated, and the physician had little to aid him, 
apart from his patient's faith in him, laudanum, alcohol, and, in certain cases, the saw.* 

Any ethnobotanic value such claims as those listed above may hold are obviated by the 
lack of information as to the origin of the claim, the cultural groups that used the plant for 
the claimed purpose, the extent of such use, and the historic period of such use. Herbal 
names are introduced without indication of those that may have been used as synonyms by 
one group or usages that may have been separated by centuries or continents. 

Even books by academic writers are not exempt from the above strictures. Thus, one such 
book describes comfrey without mentioning its hepatotoxicity and carcinogenicity. Indeed, 
it makes the statement, "toxicity is unlikely even after ingestion of moderately large quan- 
tities." 216 According to this source, North American Senecio does not seem to be as toxic 
as Senecio grown elsewhere. In a writer from the American West, it is disturbing to read 
unqualified statements such as chamomile being Anthemis nobilis. In Europe, and perhaps 
on the East Coast, this plant is sold as Roman chamomile. In the West, typically A. cotula 
is sold as chamomile, or manzanilla. The common manzanilla in Mexico, however, is 
Matricaria, typically sold in Europe as German chamomile. Such regional niceties are usually 
ignored by writers of herbals, but are of importance to pharmacologists and ethnobotanists. 

There are, of course, exceptions. One of the finest of the books addressed to the lay 
reader is that of Tyler's. 217 This examines the evidence underlying claims made for plants 
and draws rational conclusions. Morton" covers a limited geographical area, but provides 
a useful and exhaustive data base despite the tortured layout. A more conventional typography 
is used in her related volume which, despite its title, deals not with the Netherlands, but 
with the herbs of the Carolina coast. 218 

In the U.S., plants sold as herbs or food supplements fall into a regulatory void. They 
are neither food nor drugs, so there is no requirement that they conform to the cleanliness 
standards for foods or the high standards of safety and efficacy demanded of drugs. 14 - 219 In 
general, however, the public does not realize this. Toxic plants are being sold, and plants 
are frequently misidentified. 

* It will be recalled that "sawbones" was the vulgar sobriquet used by the aspiring medical students in "The 
Pickwick Papers" to refer to the eminent in their profession. Virginia Woolf. in her diary for March 6. 1935. 
describes the "affability and character of the old saw bones Tonks." the aforesaid Tonks looking like a doctor 
even though he was not one. 



352 



78 Toxicants of Plant Origin 

standing into the values and belief systems of such society, so can a study of our own 
society. 

At-risk groups for the use of herbs include the very young, the very old, the ill, those 
who take a wide variety of herbal preparations on a regular basis, and those who take a 
large quantity of any one herb. The solutions are obvious. How to get people to follow 
them, however, is problematic. Some simple guidelines to reduce risk are: 

1. Do not give herbs to babies. 

2. Do not take a large quantity of any one preparation. 

3. Only buy preparations on which the plants are listed on the packet (no guarantee of 
safety or correctness, but at least a start). 

4. Do not take anything containing comfrey. 

The features by which a plant may be identified are typically obscured or destroyed during 
its conversion to an herbal form (Figures 1 to 3). Thus, regulation as to species must occur 
before this point. When a botanical binomial does appear on a packet, it is frequently 
incorrect. Even major companies in America have sold plants incorrectly identified. Diffi- 
culties with the use of nonscientific names have been discussed elsewhere. 1 * Even scientists 
tend to have an unreasonable expectation that the domain of meaning of a herbal name 
should coincide with that of a botanically established species, and that it should therefore 
stand in a one-to-one correspondence with a botanical binomial. The history of botanical 
nomenclature itself, a continual War of the Roses ebbing and flowing between lumpers and 
splitters, should provide a sufficient indication that the boundaries of a species are highly 
mutable even within science. When it comes to translations between herbal and scientific 
names, profound confusion is all but inevitable. Within a circumscribed geographic area, 
three botanical species have been established as being sold under the herbal name gordolobo 
verba; one of these, Verbascum thapsus, in turn, is sold under at least seven herbal names. 14 
Morton 65 lists 2 1 names from the Caribbean area under which the toxic plant Heliotropium 
curassavicum is sold. Vernacular names range from the English sailors tea, seaside heli- 
otrope, and wild lavender, to Spanish names such as alacrancillo, carna de sapo, or pata de 
galio. H. indicum, also used herbally in the Caribbean and also toxic, has a pedigree of 38 
vernacular names. A further example, if one is needed, is the list of synonyms by which 
Cimicifuga racemosa is known in Carolina. Croom 221 has found that black snakeroot, cohosh, 
squawroot, blueberry, yellow ginseng, columbine leaved leontice, nchweed, rattleroot, bug- 
bane, and a whole host of other names are used to refer to this plant. To complicate matters, 
black snakeroot is also used in the same area as the common name for Asarum canadense, 
Sanicula canadensis, and S. marilandica. Croom glosses this with a revealing warning: 
"Many nonbotanists desiring to assign a scientific name to a common name generally ask 
a botanical taxonomist for advice or look up the common name in a botanical manual. As 
shown from the above diversity of plant names, the scientific name applied from these 
approaches is easily subject to error, and more dangerously, adds an illusion of accuracy to 
the data. ""' The paper of Croom, by the way, is an excellent description of how to investigate 
herbal remedies. 

In view of the nomenclatural confusion, and the unreliability of labeling, it is of the 
utmost importance in any suspected pyrrolizidine poisoning to obtain plant samples and have 
them identified by a properly qualified botanist and to establish the presence of PAs in the 
sample by chemical analysis. With many of the literature cases classified as pyrrolizidine 
poisoning, one or both of these fundamental steps has been omitted. 

Contamination of food grains occurs in countries unblighted by widespread application 
of weed killers. Control is, in principle, simple. Seeds of plants causing most of the problems, 
such as Heliotropium, Senecio, and Crotalaria, are smaller than those of the food grain they 



353 



80 Toxicants of Plant Origin 

19. Hogan, R. P., Hemorrhagic diathesis caused by drinking an herbal tea, J. Am. Med. Assoc. 2679, 1983. 

20. Bras, G. and Hill, K. R.. Veno-occlusive disease of the liver. Lancet. 161, 1956. 

21. Stuart, K. L. and Bras, G., Veno-occlusive disease of the liver. Q. J. Med.. 26, 103, 1957. 

22. JellifTe, D. B., Bras, G., and Stuart, K. L., Veno-occlusive disease of the liver. Pediatrics, 14, 334, 
1954. 

23. JellifTe, D. B., Bras, G., and Stuart, K. L., The clinical picture of veno-occlusive disease of the liver 
in Jamaican children, Ann. Trop. Med. ParasitoL, 48, 386, 1954. 

24. Stuart, K. L. and Bras, G., Clinical observations on veno-occlusive disease of the liver in Jamaican 
adults, Brit. Med. J.. 2. 348, 1955. 

25. Shvastava, R. N., Mohabbat, O., Ghani, A. R., and Aram, G. N., Veno-occlusive disease of the liver, 
Indian Pediatr.. 15, 143, 1978. 

26. McLean, E. K. and Mattocks, A. R., Environmental liver injury — plant toxins, in 7acic Injury of the 
Liver. Part B. Farber, E. and Fisher. M. M., Eds., Marcel Dekker. New York. 1980, 517. 

27. Lafranconi, M. and Huxtable, R. J., Pyrrolizidines and the pulmonary vasculature. Rev. Drug Metab. 
Drug Interact.. 3, 271, 1981. 

28. Huxtable, R. J., Ciaramitaro, D., and Eisenstein, D., The effect of a pyrrolizidine alkaloid, monocro- 
taline, and a pyrrole, dehydroretronecine, on the biochemical functions of the pulmonary endothelium. Mot. 
Pharmacol.. 14, 1189, 1978. 

29. Lafranconi, W. M., Duhamel, R. C, Brendel, K ... and Huxtable, R. J., Differentiation of the cardiac 
and pulmonary toxicity of monccrotaline, a pyrrolizidine alkaloid, Biochem. Pharmacol.. 33, 191, 1984. 

30. Huxtable, R. J., Paplanus, S., and Laugbarn, J., The prevention of monocrotaline-induced right ven- 
tricular hypertrophy. Chest. 71S, 308S, 1977. 

31. Allen, J. R. and Chesney, C. F., Effect of age on development of cor pulmonale in non-human primates 
following pyrrolizidine alkaloid intoxication, Exp. Mol. Pathol., 17, 220, 1972. 

32. Laird, H. E. and Huxtable, R. J., Comparative cardiopulmonary changes in the rat and rabbit following 
subacute exposure to pyrrolizidine alkaloid. Pharmacologist, 20 (Abstr.), 178, 1978. 

33. Heath, D., Shaba, J., Williams, A., Smith, P., and Kombe, A., A pulmonary hypertension-producing 
plant from Tanzania, Thorax. 30, 399, 1975. 

34. Hill, K. R., Rhodes, K., Stafford, J. L., and Aub, R., Liver disease in Jamaican children (serous 
hepatosis), West Indian Med. J., 1, 49, 1951. 

35. Stillman, A. E., Huxtable, R., Consroe, P., Kohnen, P., and Smith, S., Hepatic veno-occlusive disease 
due to pyrrolizidine poisoning in Arizona, Gastroenterology, 73, 349, 1977. 

36. Fox, D. W.. Hart, M. C, Bergeson, P. S., Jarrett, P. B., Stillman, A. E., and Huxtable, R. J., 
Pyrrolizidine (Senecio) intoxication mimicking Reye's syndrome, J. Pediatr.. 93, 980, 1978. 

37. Huxtable, R. J., Problems with pyrrolizidines. Trends Pharm. Sci.. 1, 299, 1980. 

38. Hsu, I. C Robertson, K. A., and Allen, J. R., Tissue distribution, binding properties and lesions 
produced by dehydroretronecine in the nonhuman pnmate. Chem. Biol. Interact.. 12, 19, 1976. 

39. Hsu, I. C, Shumaker, R. C, and Allen, J. R. , Tissue distribution of tritium-labeled dehydroretronecine, 
Chem. Biol. Interact.. 8, 163, 1974. 

40. Ismailov, N. I., Madzhidov, N. M., Magrupov, A. L., and Makhkamov, G. M., and Mukminova 
Sh., G., Klmika. diagnostika i lecheniye, trichodesmotokikoza (alimentarno toksicheskogo entsefalita) 
[Clinical signs, diagnosis and treatment of Trichodesma toxicosis (alimentary toxic encephalopathy)], Med- 
itsina. Tashkent. Uzbek S.S.R., 1970, 85. 

41. Candrian, U. R. S.. Luthy. J., and Schlatter, C, In Vivo covalent binding of retronecine-labelled [>H] 
seneciphylline and [ 3 H] seneciomne to DNA of rat liver, lungs and kidney, Chem. Biol. Interact., 1, 1985. 

42. Carstens, L. A. and Allen, J. R., Arterial degeneration and glomerular hyalinization in the kidney of 
monocroialine-intoxicaied rats. Am. J. Pathol.. 60, 75. 1972. 

43. Hooper, P. T., Experimental acute gastrointestinal disease caused by the pyrrolizidine alkaloid, lasiocarpine, 
J. Comp. Pathol.. 85. 341. 1975. 

44. Van der Watt, J.J. and Purchase, I. F. H., The acute toxicity of retrorsine, aflatoxin and sterigmatocysun 
in vervet monkeys, Br. J. Exp. Pathol., 51, 183, 1970. 

45. Peterson, J. E., Samuel, A., and Jago, M. V., Pathological effects of dehydroheliotridine, a metabolite 
of hehotndine-based pyrrolizidine alkaloids, in the young rat, J. Pathol., 107, 175, 1972. 

46. Lafranconi, W. M., Onkuma, S.. and Huxtable, R. J., Biliary excretion of novel pneumotoxic metabolites 
of the pyrrolizidine alkaloid, monocrotaline, Toxicon. 23, 983, 1985. 

47. Lafranconi, W. M. and Huxtable, R. J., Hepatic metabolism and pulmonary toxicity of monocrotaline 
using isolated perfused liver and lung, Biochem. Pharmacol., 33, 2479, 1984. 

48. White, I. N. H., Excretion of pyrrolic metabolites in the bile of rats given the pyrrolizidine alkaloid 
retrorsine or the bis-A'- ethylcarbamate of synthanecine A, Chem. Biol. Interact., 16, 169, 1977. 

49. Jago, M. V., Lanigan, G. W ., Bingley, J. B., Pierey, D. W. T., Whitten, J. H., and Titchen, D. A., 
Excretion of the pyrrolizidine alkaloid heliotnne in the unne and bile of sheep, J. Pathol., 98, 1 15, 1969. 



354 



82 Toxicants of Plant Origin 

83. Krishnamachari, K. A. V. R., Bhat, R. V., Krishnamurthi, D., Krishnaswamy, K., and Nagarajan, 

V., Aeuopathogenesis of endemic ascites in Sarguja distnct of Madhya Pr?desh. Indian J. Med. Res., 65, 
672. 1977. 

84. Tandoo, B. N., Tandon, H. D.. Taadon, R. K., Narendranathan, M., and Joshi, Y. K., Epidemic 
of veno-occlusive disease in central India, Lancet. August, 271, 1976. 

85. Siddiqi, M. A., Suri, K. A., Suri, O. P., and Atal, C. K., Genus Crotalana: pan 34 — cronabumune, 
a new pyrrolizidine alkaloid from Crotalana nana burnt, Indian J. Chem.. 16B, 1132, 1978. 

86. Siddiqui, M. A., Suri, K. A., Suri, M. P., and Atal, C. K., Novel pyrrolizidine alkaloid from Crotalana 
nana. Photochemistry. 17, 2143. 1978. 

87. Partridge, E., Origins: A Shon Etymological Dictionary of Modern English. Greenwich House, New York, 
1983. 

88. Culvenor, C. C. J., Clarke, M., Edgar, J. A., Frahn, J. L., Jago, M. V., Peterson, J. E., and Smith, 
L. W., Structure and toxicity of the alkaloids of Russian comfrey (Symphytum X uplandicum Nyman), a 
medicinal herb and item of human diet, Experientia (Basel). 36, 377, 1980. 

89. Furuya, T. and Araki, K., Studies on constituents of crude drugs. I. Alkaloids of Symphytum officinale 
Linn., Chem. Pharm. Bull., 16, 2512. 1968. 

90. Furuya, T. and Hikichi, M., Constituents of crude drugs. D. Alkaloids and tnterpenoids of Symphytum 
officinale, Phytochemistry. 10. 2217, 1971. 

91. Culvenor, C. C. J., Edgar, J. A., Frahn, J. L., and Smith, L. W., The alkaloids of Symphytum X 
uplandicum (Russian comfrey), Aust. J. Chem.. 33, 1 105, 1980. 

92. Mattocks, A. R., Toxic pyrrolizidine alkaloids in comfrey. Lancet. November, 1136, 1980. 

93. Roitman, J. N., Comfrey and liver damage. Lancet. April, 944, 1981. 

94. Hirono, I., Mori, H., and Haga, M., Carcinogenic activity of Symphytum officinale. J. Natl. Cancer 
Inst.. 61, 865. 1978. 

95. Svoboda, D. and Reddy, J. K., Malignant rumours in rats given lasiocarpine. Cancer Res.. 32, 908, 
1972. 

96 Hirono, I., Haga, M., Fujii, M., Matsuura, S., Matsubara, N.. Nakayama, M., Furuya, T., Hikichi, 
M., Takanashi, H., Uchida, E., Hosaka, S„ and Ueno, I., Induction of hepatic tumors in rats by 
senkirkine and symphytine. J. Natl. Cancer Inst.. 63, 469, 1979. 

97. Clapham, A. R., Turin, T. C, and Warburg, E. F., Flora of the British Isles, Cambridge University 
Press, London, 1962. 

98. Hills, L., Comfrey. Past, Present and Future. Faber and Faber, London, 1976. 

99. Anon., Warning on comfrey, Br. Med. J.. 1, 598, 1979. 

100. Leung, A. Y., Encyclopedia of Common Natural Ingredients Used in Foods, Drugs and Cosmetics. John 
Wiley & Sons, New York. 1980. 

101. HUls, L., Comfrey — Fodder. Food and Remedy. Universe Books, New York. 1976. 

102. Brauchli. J., Luthy, J., Zweifel, U., and Schlatter, C, Pyrrolizidine alkaloids from Symphytum officinale 
L and their percutaneous absorption in rats, Experientia, 38, 1085, 1982. 

103. Duke, J. A., Handbook of Medicinal Herbs. CRC Press, Boca Raton, FL, 1985. 

104. Bianchini. F. and Corbetta, F., Health Plants of the World: Atlas of Medicinal Plants. Newsweek Books. 
New York. 1979. 

105. Culpepper, N., The English Physician Enlarged, with Three Hundred and Sixty-Nine Medicines made of 
English Herbs. A. and J Churchill, London. 1708. 

106. Rickett, H. W., Wild Flowers of the United States. Vol. 2 (Part 2), McGraw-Hill, New York. 1975. 
407. Hutchens, A. R., Indian Herbology of North America, 9th ed., Merco. Windsor, Ontario, 1983. 

108 Huxtable. R. J., Luthy, J., and Zweifel, U., Toxicity of comfrey-pepsin preparations. New Engl. J. 
Med., 315. 1095. 1986. 

109. Ridker, P. M., Ohkuma, S., McDermott, W. V., Trey, C. and Huxtable, R. J., Hepatic veno- 
occiusive disease associated with the consumption of pyrrolizidine-containing dietary supplements. Gas- 
troenterology. 88. 1050. 1985. 

110. Huxtable, R. J., Luthy, J., and Zweifel, U., Unpublished observations. 

111. Huxtable, R. J., Unpublished observation;. 

1 12. Aprill, C, Personal communication. 

113. HartweU, J. L., Plants used against cancer. A survey, Uoydia. 30. 379. 1967; 31. 71, 1968; 32, 79, 1969; 
32. 153, 1969. 32. 247. 1969; 33. 97. 1970; 33. 288. 1970; 34. 103, 1971; 34, 204, 1971; 34. 310. 1971; 
34,386. 1971. 

114. Schoental, R., Health hazards of pyrrolizidine alkaloids: Toxicol. Lett., 10, 323. 1982. 

115. Braginskii, B. M. and Bobokhodxaev, I., Hepatosplenomegaly against the background of heliotropic 
toxicosis. Sov Med., 28. 57. 1965 

1 16 Sawina, K. L., Pathological anatomy of atrophic hepatic cirrhosis. Arkh. Pawl.. 14, 65, 1952. 

117. Dubrovinski, S. B., About the alimentary toxicosis caused by heliotrope. J. Sov. Prot Health. 6. 1946 



355 



84 Toxicants of Plant Origin 

149. Moennan, D. E., American Medical Ethnobotany: A Reference Dictionary, Garland. New York, 1977, 
527. 

150. Bennett, W. C. and Zingg, R. M., The Tarahumara: An Indian Tribe of Northern Mexico. Rio Grande 
Press. Gloneta. NM. 1976. 

151. Willmot, F. C. and Robertson, G. W., Senecio disease, or cirrhosis of the liver due to senecio poisoning. 
Lancet, p. 848, 1920. 

152. Selzer, G. and Parker, R. G. F., Senecio poisoning exhibiting as Chiari's syndrome. Report of twelve 
cases. Am. J. Pathol.. 27. 885. 1951. 

153. AJ-Hasany, M. and Mohamed, A. S., Veno-occlusive disease of the liver in Iraq, Arch. Dis. Child.. 45, 
722, 1970. 

154. Huxtable, R., Stillman, A., and Ciaramitaro, D., Characterization of alkaloids involved in human Senecio 
(pyrrolizidine) poisoning, Proc. West. Pharmacol. Soc. 20, 455, 1977. 

155. Meneses-Vionet, A., Personal communication. 

156. Drewes. S. E. and Kaye, P. T., The long road of the Senecio alkaloids. S. Afr. J. Sci., 81, 455, 1985. 

157. Margalith, D., Heraief. E., Schiiidler, A. M., Birchler. R., Mosimann, F., Aladjero, D.. and Gonvers. 
J. J., Veno-occlusive disease of the liver due to the use of tea made from senecio plants, J. Hepatol., 204, 
1985. 

158. Bras, G., Aspects of hepatic vascular disease, in The Liver, Gall. E. A. and Mostofi, T. K., Eds., Williams 
& Wilkins. Baltimore, 1973, 406. 

159. Wunn, H., Gehauftes auftreten einer Endophlebitis Hepatica obliterans in Saulingsalter, Klin. Wochestr, 
18. 1527. 1939. 

160. Hashem, M., Etiology and pathology of type of liver cirrhosis in Egyptian children, J. Egypt. Med. Assoc, 
22, 319. 1939. 

161. Hashem, M., Etiology and pathology of types of liver cirrhosis in Egyptian children, J. Egypt. Med. 
Assoc. 35, 1. 1952. 

162. Shukry, H., Awwad, S., and Hashem, M., Fatty liver disease among improperly weaned Egyptian 
children. Gaz. Egypt. Pediatr Assoc, 1,1, 1952. 

163. Awwad, S., The Budd-Chian syndrome. J. Egypt. Med. Assoc. 35, 650, 1952. 

164. El Gholmi. A., El Nabawy, M., Khattab, M., Shukry, A. S., Gabr, M., El Sibaie, B., Aidaros, S., 
and Soliman, L., Infantile liver cirrhosis of Egypt, Gar. Egypt. Pediatr. Assoc, 4, 320, 1956. 

165. Safouh, M. and Shehata, A. H.. Hepatic vein occlusion disease of Egyptian children. J. Pediatr., 67, 
415, 1965. 

166. Stein, H., Veno-occlusive disease of liver in African children. Br. Med. J.. 1496, 1957. 

167. Stein, H. and Isaacson, C., Veno-occlusive disease of liver. Br. Med. J., 372, 1962. 

168. Scott, R. B... Budinger, J. M., Prendergast, R. A. M., and Nydick, I., Hepatic veno-occlusive syndrome 
in an American adult. Gastroenterology. 42. 631, 1962. 

169. Gupta, P. S., Gupta, G. D., and Sharma, M. L., Veno-occlusive disease of the liver, Br. Med. J.. I, 
1184, 1963. 

170. Tandon, B. N., Tandon, H. D., Bhatia, M. L., Bargavas, S.. Lai, P.. and Aurora, R. R., Study of 
an epidemic of veno-occlusive disease in India, Gut. 17. 849, 1976. 

171. Tandon, H. D., Tandon, R., and Nayak, N. C, Pathological study of liver in an epidemic outbreak of 
veno-occlusive disease, Indian J. Med. Res., 65. 679, 1977. 

172. Hou Jinqui, Xia Yudin, Yu Zhanshi, An Yan, and Tang Yixai, [Veno-occlusive disease of the liver 
with report of 2 cases]. Chung Hua Nei ko Tsa Chih, Chinese J. Int. Med.. 19, 187, 1980. 

173. Huxtable, R. J. and Halka, J., Unpublished observations. 

174. Ghanem, J. and Hershko, C., Veno-occlusive disease and primary hepatic vein thrombosis in Israeli 
Arabs. Isr. J. Med. Sci., 17, 339, 1981. 

175. Moennan, D. F., The Medicinal Plants of Native America, Vol. 1 and 2, University of Michigan Press, 
Ann Arbor, 1986 

176. Broch-Due, A. I. and Aasen, A J., Alkaloids oi Anchusa officinalis L. Identification of the pyrrolidine 
alkaloid lycopasanune. Acta Chem. Scand. Ser. B. 34, 1980. 

177. Furuya, T., Murakami, K., and Hikichi, M., Constituents of crude drugs. II. Senkirkine, a pyrrolizidine 
alkaloid from Farfugium japontcum. Phytochemistry, 10. 2217, 1971. 

178. Asada, Y. and Furuya, T., Studies on constituents of crude drugs. XV. New pyrrolizidine alkaloids from 
Ligularta dentaia. Chem. Pharm. Bull, 32, 475, 1984. 

179. Hirono. I., Shimizu, M., Fushimi, K., Mori, H.. and Kato, K., Carcinogenic activity of Petasites 
japomcus Maxim, a kind of coltsfoot, Gann Monogr. Cancer Res.. 64. 527, 1973. 

1 80. Hichiki. M. and Furuya, T., Studies on constituents of crude drugs. VII. Syneilesine and acerylsyneilesine 
from Syneilesis palmaia. Chem. Pharm. Bull.. 24. 3178, 1976. 

181. Culvenor, C. C. J., Edgar, J. A., Smith, L. W., and Hirono, I., The occurrence of senkirkine in 
Tussilago farfara. Aust. J. Chem.. 29. 229. 1976. 



356 



86 Toxicants of Plant Origin 

212. White. R. D., Krumperman, P. H., Cheeke, P. R., Dcinzer, M. L., and Buhler, D. R.. Mutagenic 
response of tansy ragwort (Senecw jacobaea) plant, pyrrolidine alkaloids and metabolites in goat milk 
with the salmonella/ mammalian-microsome mutagenicity test, J. Anim. Sci., 58, 1245, 1984. 

213. Wheelwright, E. G., Medicinal Plants and their History. Dover Publications, New York. 1974. 
214 Christopher, J. R., School of Natural Healing. Christopher Publications. Spnngsfield, UT. 1976. 

215. Santillo, H., Natural Healing With Herbs. Hohm Press. Prescott Valley. AZ. 1984. 

216. Spoerke, D. G., Herbal Medications. Woodbndge Press. Santa Barbara, CA, 1980. 

217. Tyler, V. E., The Honest Herbal: A Sensible Guide to the Use of Herbs and Herbal Remedies. G. F. 
Stickley. Philadelphia, Undated. 

218. Morton, J. F., Folk Remedies of the Low Country. E. A. Seeman, Miami. 1974 

219. Lewis, W. H., Reporting adverse reactions to herbal lngestams, J. Am. Med. Assoc. 240. 109, 1978. 

220. Lipsitz, D. J., Herbal teas and water intoxication in a young child, J. Fam. Praci.. 18, 933, 1984. 

221. Croom, E. M., Documenting and evaluating herbal remedies. Econ. Bot.. 37, 13, 1983. 

222. Pederson, E., Pyrrolizidine alkaloids in Danish species of the family Boraginaceae, Arch Pharm Chem 
Sci. Ed.. 3, 55, 1955. 



357 



510 



HEPATOLOGY ELSEWHERE 



Hf.patolocy 



HUMAN EMBRYOTOXICITY OF 
PYRROLIZIDINE-CONTAINING DRUGS 

Roulet M, Laurini R, Rivier L, Calame A. Hepatic veno- 
occlusive disease in newborn infant of a woman drinking 
herbal tea. J Pediatr 1988; 112:433-436. 

ABSTRACT 

Hepatic veno-occlusive disease is the most fre- 
quent cause of hepatic vein obstruction in children. 
Only the small and medium veins are involved. 
The initial vascular lesion is endothelial edema, 
followed by phlebosclerosis and occlusion of the 
small vessels, leading to secondary necrosis of 
liver cells, progressive fibrosis, and ultimately cir- 
rhosis. The disease was first recognized in Jamaica 
in 1954, and subsequently reported from other 
parts of the world. It arises from the ingestion of 
pyrrolizidine alkaloids found in various herbal 
medicines and in poorly winnowed wheat. Several 
plants have been implicated, in particular the gen- 
era Senecio, Crotalaria, and Heliotropium. More 
recently, similar pathologic changes have been ob- 
served after hepatic irradiation, bone marrow 
transplantation, and use of chemotherapeutic 
drugs. We report a newborn infant with fatal he- 
patic vaso-occlusive disease. Pyrrolizidine alka- 
loids were identified in the herbal medicine bought 
by the mother at a pharmacy and consumed daily 
during the entire pregnancy. 

COMMENTS 

Venoocclusive disease (Fig. 1) was first recognized as 
a clinical entity 30 years ago in the West Indies (1). It is 
a highly characteristic finding which can be considered 
pathognomonic of pyrrolizidine alkaloid (PA) poisoning. 
It occasionally occurs as a consequence of chemotherapy 
with drugs such as cytarabine, but, apart from these 
substances, no other cause is known. In venoocclusive 
disease, there is occlusion of the small branches of the 
hepatic veins, leading to ascites, edema and reduced 
urinary output. It typically occurs in young children 
intentionally given PA-containing plants as foods or 
herbs, or accidentally exposed as a result of contamina- 
tion of grain with the seeds of PA-containing plants (2). 
The scope of the problem is indicated by the fact that at 
least 160 toxic PAs are known, scattered in over 330 
plant species worldwide. 

PA poisoning has been attributed to Crotalaria, Sym- 
phytum, Heliotropium, Trichodesma and Senecio species 
(3). This report is the first attribution to the widely used 
herb, Tussilago farfara. The patient's mother purchased 
the tea containing this material from a pharmacy. Also, 
this is also the first identification of the PA senecionine 
as the primary alkaloid involved in a human poisoning. 
Of more significance, this is also the first report of human 
intoxication as the result of fetal exposure. However, 
senecionine has long been known to be embryotoxic to 
laboratory animals (4). 

Many clinical reports on PA poisoning lack identifi- 




FlG. 1. Ascites associated with venoocclusive disease in the West 
Indies in a five-year-old child. This figure is taken from Ref. (1) and 
reprinted by permission from the U.S. and Canadian Academy of 
Pathology, © 1973. 



cation of the plant material consumed, and information 
about alkaloid content. In most cases, dose calculations 
were not done. These criticisms also apply to this paper. 
However, we have been given enough information to 
make approximate calculations. The woman drank one 
cup of tea per day throughout pregnancy. The tea con- 
tained 0.6 mg senecionine per kg dry weight, and the 
baby was delivered at 36 weeks gestation, weighing 2.74 
kg at birth. The average American tea bag contains 2.72 
gm of tea. If we use this figure to calculate the tea 
consumed by the mother, a total alkaloid intake of 0.343 
mg may be calculated. If we assume that all of the 
alkaloid had been delivered to the baby, by birth she 
would have had a cumulative exposure of 0.125 mg per 
kg. To facilitate comparison between PAs having differ- 
ent toxicities, it is convenient to express exposure as rat 
LDso units (5). The LD^ ( , of senecionine is 50 mg per kg 
(6), so the child received a cumulative dose of approxi- 
mately 0.0025 rat LD W units. This is an extremely low 
dose. However, it may be compared to doses received in 
other cases of PA poisoning. Deaths have occurred in 
babies who received total doses of 0.34 rat LD -„, units of 
retrorsine over a 4- to 40-day period [i.e. these children 
probably received supralethal dose (3)], and to adults 
receiving an approximate intake of 0.017 rat LD -.„ units 
of heliotrine over a 6-month period (7). A cumulative 
intake of 0.014 rat LD-,,, units of symphytine over a 4- 



358 



Vol. 9. No. 3. 1989 



HEPATOLOGY ELSEWHERE 



511 



month period produced venoocclusive disease and portal 
hypertension in an adult (8). 

It appears, therefore, that in general humans are more 
susceptible to PA poisoning than are rats. Toxicity is 
exacerbated when small doses are given over a prolonged 
period of time, and babies are particularly vulnerable to 
the dangers of such low-level exposure. In this case, the 
mother incurred no clinically apparent harm in taking a 
tea which was seriously toxic and ultimately fatal to her 
child in utero. 

Despite the frequent demonstration of PA poisoning, 
and the vast scientific literature on the topic, there is 
still a lack of recognition in the United States as to the 
dangers. Of particular public health significance is the 
widespread use of comfrey pepsin pills and capsules, and 
related preparations, as digestive aids. Depending on the 
alkaloid content of the particular batch purchased, rou- 
tine use of such preparations can lead to toxic exposures 
within a matter of days (9). Our Canadian neighbors 
have exhibited more caution in this regard by banning 
preparations containing comfrey root or certain muta- 
genic PAs. 

Ryan J. Huxtable, Ph.D. 
Department of Pharmacology 



College of Medicine 
Health Sciences Center 
Tucson, Arizona 85724 



REFERENCES 

1. Bras G. Aspects of hepatic vascular diseases. In: Gall EA. Mostofi 
FK. eds. The liver. Baltimore: Williams & Wilkins. 1973: 406-430. 

2. Huxtable RJ. Herbal teas and toxins: novel aspects of pyrrolizidine 
poisoning in the United States. Perspect Biol Med 1980; 24:1-14. 

3. Huxtable RJ. Human health implications of pyrrolizidine alkaloids 
and herbs containing them. In: Cheeke P, ed. Toxicants of plant 
origin. Boca Raton, Florida: CRC Press, 1989: in press. 

4. Sundareson AE. An experimental study on placental permeability 
to cirrhogenic poisons. J Pathol Bactenol 1942; 54:289-298. 

5. Bull LB, Culvenor CCJ. Dick AT. The pyrrolizidine alkaloids: their 
chemistry, pathogenicity and other biological properties. Amster- 
dam: North-Holland. 1968: 293. 

6. Mattocks AR. Chemistry and toxicology of pyrrolizidine alkaloids. 
London: Academic Press, 1986: 393. 

7. Mohabbat O, Younos MS, Merzad AA. et al. An outbreak of hepatic 
veno-occlusive disease in north-western Afghanistan. Lancet 1976; 
2:269-272. 

8. Ridker PM. Ohkuma S, McDerrnott WV, et al. Hepatic veno- 
occlusive disease associated with the consumption of pyrrolizidine- 
containing dietary supplements. Gastroenterology 1985; 88:1050- 
1054. 

9. Huxtable RJ : Luthy J. Zweifel V Comfrey pepsin preparations: a 
warning (Correspondence). N Engl J Med 1986; 315:1095. 



359 



coRRE.sPONUt.scF. New Fng . J.Med 315:1095 61-586) 

TOXICITY OF COMFREY-PEPSIN PREPARATIONS 

Ta the Editor: SVe wish to draw attention to the health risks of a 
food supplement containing Symphytum that is widely available in 
the United States. Numerous brands of comfrey-pepsin capsules 
and tablets are sold in. herbal and health-food stores as a digestive 
aid. Users take them daily over long periods or even permanently. 

We have analyzed the pyrrolizidine content of two brands of 
comfrey-pepsin capsules, one brand purporting to be prepared from 
the leaves and the other from the roots of the comfrey plant. Alka- 
loids and alkaloid N-oxides were isolated by the method of Brauchli 
et al., 1 and the resulting extracts analyzed by thin-layer chromatog- 
raphy and gas chromatography— mass spectrometry.' The brand 
made from the roots contained 520 to 590 mg per capsule, with a 
pyrrolizidine content of 400 mg-kg"' and an N-oxide content of 
2500 mg-kg - ' (total pyrrolidines, 2900 mg-kg - '). The N-oxide 
fraction consisted of the N-oxides of symphytine and symglandine. 
the isomeric pairs 7-acetylintermedine plus 7-acetyllycopsamine, 
and intermedine plus lycopsamine. The free alkaloid fraction con- 
tained the same substances with the addition of 7- and 9-angdoyl- 
retronedne. The brand made from the leaves contained 40 mg-kg"' 
of free alkaloids and 230 mg-kg"' of N-oxides (total pyrrolizidines, 
270 mg-kg"'). The free alkaloid fraction contained 7-acetylinter- 
medine/7-aceiyllycopsamine and lycopsamine. The N-oxide frac- 
- tion contained the N-oxides of 7- and 9-angeloylretronecine. The 
chromatographic identifications of lycopsamine, intermedine, and 
7-acetylintermedine were confirmed by mass spectrometry. 

These alkaloids are hepatotoxic, and some of them are demon- 
strated carcinogens. " A person consuming rwo capsules per meal 
for six months would receive a total of 162 mg of alkaloids from the 
"leaf preparation and 1740 mg from the "root" preparation. He- 
patic veno-ocdusive disease (the Budd-Chiari syndrome) is pa- 
thognomonic of pyrrolizidine toxidry. Veno-ocdusive disease has 
been reported in a woman who took rwo tablets of a comfrey— pepsin 
preparation per meal for four months. 6 In that case, it was estimat- 
ed that the patient had consumed a total of 85 mg of alkaloids — the 
equivalent of nine days' use of the "root" preparation. 

The disturbing aspects of our findings include the widespread use 
of comfrev and the fact that "normal" use of the preparation can 
readilv result in the ingestion of toxic quantities of pyrrolizidines. 

Ryan J. Hlxtabl£. Ph.D. 

University of Arizona 

Tucson, AZ 85724 College of Medicine 

JCrc LCthy, Ph.D. 
Berne, Switzerland Public Health Department 

Ulkich Zwejfel. Ph.D. 

Eidgenossischen Technischen 

Zurich. Switzerland Hochschule 

1. Brauchli J. Luihy I. Zweifel U. Schlatter C. Pyrroliudint alkaloids from 
Sympnvrum officinale L. ud their percutaneous absorption m rats. Expenen- 
tu 1982;38:1083-7. 

2. Luihy 1. Brauchli J. Zweifel U. Schmid P. Schlatter C Pynolizidin-Alka- 
loide in Arzneipnanzen der Boraginaceen: Bongo officinalis l_ und Pulmo- 
runa officinalis L. Pharm Acta Helv 1984: 59-_242-6. 

3. Culvenor CCI. Clark M. Edgar 1A, ct al. Structure and loaicity of the 
alkaloids of Russian comfrey [Symphytum x npiandicumNyman). a medici- 
nal herb and item of human diet. Expeneana 1980-. 36:377-9 

4. Hirono I. Mon H. Haga M. Circtnogetre activity of Sympmyrum officinale. 
JNCI 1978: 61:863-9. 

3. Hirono I. Haga M. Fojii M. et al. Inducooa of hepaoc tumors in rats by 
senkirkine and symphynne. JNCI I979-. 63:469-71. 

6. Ridker PM. Ohkuma S. McDermoct WV. Trey C. Hiutable RJ. Hepatic 
venocclusive disease associated with me consumption of pyrrol izidine- 
containing dietary supplements. Gasmwarjotogy 1983: 88:1030-1 



360 



GASTROENTEROLOGY 1985.88: 1050-4 



Hepatic Venocclusive Disease Associated 
With the Consumption of Pyrrolizidine- 
Containing Dietary Supplements 

PAUL M. RIDKER, SEITARO OHKUMA. 
WILLIAM V. McDERMOTT, CHARLES TREY, and 
RYAN f. HUXTABLE 

Harvard Medical School. Boston. Massachusetts: Department of Pharmacology. University of 
Arizona. Health Sciences Center. Tucson. Arizona; Departments of Surgery and Medicine. Nexv 
England Deaconess Hospital. Boston, Massachusetts 



Venocclusive disease, a form of Budd-Chiari syn- 
drome, was diagnosed in a 49-yr-old woman. The 
patient had portal hypertension associated with 
obliteration of the smaller hepatic venules. A iiver 
biopsy specimen showed centrilobular necrosis and 
congestion. Anaiysis of food supplements the wom- 
an regularly consumed showed the presence of pyr- 
rolidine alkaloids. The major source was a powder 
purporting to contain ground com/rey root (Symphy- 
tum sp). We calculated that during the 6 mo before 
the woman was hospitalized, she had consumed a 
minimum of 85 mg of pyrrolidine alkaloids f 15 pgi 
kg body wt ■ day). The clinical and analytic /indings 
were consistent with chronic pyrroiizidine intoxica- 
tion, indicating that low-level, chronic exposure to 
such alkaloids can cause venocclusive disease 

The pyrroiizidine alkaloids comprise a group of 
some 200 substances, many of which are hepatotox- 
ic. These alkaloids are widely distributed, both bo- 
tanically and geographically. Pyrroiizidine poison- 
ing is endemic in many areas, including Jamaica and 
many parts of Africa. Epidemics of pyrroiizidine 
poisoning have occurred in Afghanistan (1) and 
India (2). The plants responsible have been mainly 
Heiiotropium, Senecio. and Crotaiana species. 

Pyrroiizidine poisoning of humans is not well 
documented in the United States. Intoxications have 
recently been reported for the Southwestern states in 



Received July 18. 1984 Accepted October 26. 1984. 

Address requests for reprints to: Dr. Ryan |. Huxtable. Depart- 
ment of Pharmacology. Universitv of Arizona. Health Sciences 
Center. Tucson. Arizona 85724. 

This work was supported by grant HI, 25254 from the National 
Institutes of Health. 

© 1985 by the American Gastroenterological Association 
0016-5085/85S3 30 



children given herbal teas prepared from the pyrroli- 
zidine-containing plant Senecio longilobus (3,4). 
Other plants in ;his genus, particularly Senecio 
jacobaea. are major causes of livestock losses in the 
Northwest Pacific states (5). 

It is known that pyrroiizidine a'k: ,d= —-n enter 
the food chain in low concentration; in milk (6,7) 
and honey (8,9). The extent of exposure, and the 
public health implications of such exposure, are 
unknown. Due to their widespread distribution, pyr- 
roiizidine alkaloids probably occur in many herbal 
preparations. Symphytum sp (comfrey), in particu- 
lar, is widely used as a herb and vegetable in North 
America. Japan, and other parts of the world. Al- 
though the presence of pyrroiizidine alkaloids in 
Symphytum sp is well established (10,11), the risks 
associated with using preparations containing Sym- 
phytum sp have not been clearly delineated. It has 
been recommended, however, that people not con- 
sume such products (12). We report herein a case of 
pyrroiizidine poisoning in an adult consuming a 
powder purportedly containing ground comfrey 
(Symphytum) roots. 

Case Report 

A 49-yr-old mother of two was admitted to the 
hospital because of progressive swelling of the abdomen 
and extremities over the preceding 4 mo. On several 
admissions at other hospitals she had undergone radiolog- 
ic, biochemical, and cytologic examinations, laparoscopy. 
and laparotomy, none oi which resulted ;n positive find- 
ings or definitive diagnosis. 

Budd-Chiari syndrome was diagnosed on the basis of a 
liver biopsy specimen that showed centrilobular necrosis 
and congestion (Figure 1) and hepatic venograms in which 
wedge pressures oi 23 mmHg with a corrected sinusoidal 
pressure of 17 mmHg were recorded, consistent with 



361 



April 19S5 



DlrJTAK\ VENOCCLUSIVE DISEASE 1051 




moderate portal hypertension There was. however, no 
demonstrable obstruction of outflow either in the retrohe- 
patic or suprahepatic vena cava or in am of the maior 
hepatic veins (Figure 2). Films taken during balloon dis- 
tention of one of the intrahepatic venous tributaries 
showed a near obliteration of the smaller hepatic venules 
and. with pressure, extravasation of the dve into the 
hepatic parenchyma (Figure 2). Because of the intractabil- 
ity of the ascites, a side-to-side portacaval shunt was 
performed: the free portal pressure was 23.5 mmHa. the 
hepatic occluded portal pressure was 22. H mmHg. and the 



postshunt preportal pressure indicated a drop to 14.0 
mmHg. These intraoperative findings confirmed the pres- 
ence of a high degree of postsinusoidal block. The patient 
had no history of a tumor, and had not suffered trauma 
before admission. Her last pregnancy had been 22 yr ago. 
Because of her fixation on health, the patient had taken no 
drugs. There was no evidence of myeloproliferative dis- 
ease, oral contraceptive use. hypercoagulative state, outlet 
obstruction, or other common causes of the Budd-Chiari 
syndrome Preoperative weight was 122 lb. On discharge 
from the hospital after dissipation of the ascites, the 



362 



1052 RJDKER ET AL. 



GASTROENTEROLOGY Vol. 88. No. -I 




Figure 2. Two phases of a retrohepatic venogram. A. When dye was injected with the balloon inflated there was no evidence of 
obstruction of major hepatic veins. B. With continued infusion, there was progressive extravasation of dye into the 
parenchyma and irregular opacification consistent with narrowing or obliteration of small intrahepatic veins. 



patient weighed 106 lb. Long-term follow-up has revealed 
no serious problems except for a transient bout of post- 
shunt encephalopathy that was related to ingestion of an 
amount of protein estimated to be >200 g in a 12-h period. 

Analyses of Food Supplements 

The patient was a heavy consumer of herbs, vita- 
mins, and "natural" food supplements. These included 
daily supplementations of vitamins C. K. E. A. and B 
complex, calcium, magnesium, potassium, zinc. iron, leci- 
thin, and sterotrophic adrenal bovine extract. She drank 
~3 cups of chamomile tea per week, and for the 6 mo 
before admission had consumed 1 qt/day of a herbal tea 
known as MLM6. In addition, for the 4 mo before admis- 
sion, she had taken two capsules of "comfrey-pepsin pills" 
with each meal. 

The "MLM6 herbal beverage with ginseng' (Erewhon 
Inc.. Boston. Mass. I and "comfrey-pepsin" capsules (Na- 
ture's Way. Provo. Utah) were analyzed for pyrrolizidine 
alkaloid content. According to the packet, the former is 
prepared in japan. 

The tea was extracted in a Soxhlet continuous extractor 
with ethanol for 20 h. The comfrev-pepsin capsules were 
opened, and the powder was extracted with boiling metha- 
nol in a round-bottomed flask for 2 h. The extracts were 
analyzed for pyrrolizidine alkaloids and pyrrolizidine X- 
oxides. as described bv Huxtable et al. (13). Monocrotaline 
was used as a standard, and pyrrolizidine concentrations 
were calculated assuming the same extinction coefficient 
(E = 48.000) and the same molecular weight for the 
unknown alkaloids as for monocrotaline The Ehrlich 



reaction used in the assay is a colorimetric procedure 
specific for hepatotoxic pyrrolizidine alkaloids (14). 

Pyrrolizidine Analyses 

Each packet of MU-16 tea contained eight 6-g tea 
bags. Samples purchased -2 yr apart were analyzed. The 
earlier sample, obtained from the patient, contained 80 
nmol pyrroliztdine/g dry wt of tea. A later sample, pur- 
chased by us. contained 23.9 nmol pyrrolizidine/g tea. and 
3.0 nmol pyrrolizidine N-oxide.g tea. Each comfrey-pepsin 
pill contained 400 mg of a white powder. The powder 
contained 107 nmol.g pyrrolizidine alkaloids and 757 
nmol/g pyrrolizidine N-oxides (Figure 3). 

The patient had consumed 480 g of MU-16 tea over a 6- 
mo period. Our analyses suggest that she had. therefore, 
consumed between 12.9 and 38.4 /imol of total pyrroli- 
dines. This is equivalent to between 0.49 to 1.45 ng'kg 
body wt ■ day. 

The patient had consumed six capsules per day of the 
comfrey-pepsin pills. Her daily consumption of pyrroli- 
dines from this source was. therefore. 2.07 jimol/day (14.1 
Aig/kg body wt ■ day). Over a 4-mo period, she had con- 
sumed -250 nmol. or 1700 ng-'kg body wt. of total pyrroli- 
zidines from the comfrey-pepsin capsules. 

Discussion 

In South Africa, it was noted many years ago 
that pyrrolizidine poisoning due to the ingestion of 
Senecio plants produced a condition similar to the 
Budd-Chian syndrome (15). Crotalana plants cause 
numerous cases of pyrrolizidine poisoning in (am.ii- 



363 



April 1985 



DIETARY VENOCCLUSIVE DISEASE 1053 






520 5*0 560 

WAVELENGTH (ni 



520 540 560 580 
WAVELENGTH Inm) 



520 540 560 560 
WAVELENGTH Inm) 



Figure 3. A. Spectrum of reaction product of authentic monocrotaline with Ehrlich reagent (5 /ig monocrotaline in a final volume of 1.1 
ml) B. Spectrum of Ehrlich reaction product of alkaloidal extract equivalent to 125 mg of comfrey-pepsin powder. C. 
Spectrum of Ehrlich rp^ction product of N-oxide fraction equivalent to 20 mg of comfrey-pepsin powder. 



ca. The highly characteristic venocclusive disease 
produced has striking similarities to the Budd- 
Chiari syndrome (16,17). 

The patient reported herein suffered a clinical 
condition suggestive of pyrrolizidine poisoning. At 
least two of the food supplements she was regularly 
consuming contain pyrrolizidine alkaloids. The vari- 
ability in content found in the MU-16 tea may be due 
to this tea consisting of a complex mixture of plants, 
the proportions of which vary from batch to batch. 
Even within a species, the content of pyrrolizidine 
alkaloids vary throughout the year, and differ be- 
tween the roots and aerial parts, and between the 
young and old leaves (18). A higher concentration of 
pyrrolizidine alkaloids was found in the comfrey- 
pepsin capsules the woman was consuming. "Com- 
frey" is Symphytum officinale, or other Symphytum 
species or hybrids. Symphytum species contain both 
pyrrolizidine alkaloids and pyrrolizidine N-oxides. 
The alkaloidal content of comfrey is highly variable. 
Mattocks (18) reporting a range for leaves of 0.003%- 
0.115%. The roots of S. asperum contain between 
0.14% and 0.4% alkaloids (19). Our analyses show 
N-oxide levels to be approximately seven times 
higher than free alkaloid levels. This underscores the 
importance of N-oxide analysis where pyTrolizidine 
poisoning is suspected, as analyzing for alkaloids 
only may give an erroneously low estimate of pyrro- 
lizidine exposure. 

The total pyrrolizidine consumption we can estab- 
lish for this patient is relatively low. It is possible 
that she had other sources of exposure, and it is 
probable that she had been consuming pyrrolizidine- 
containing supplements for longer than the period 
we could establish. We calculate a minimum daily 
intake of 700-740 fi%, or ~15 /xg/kg, over a period of 
several months. Severe liver disease has been found 
in humans with an estimated daily intake of 30-40 
Mg/kg Heliotropium alkaloids (1). In pigs, liver and 



kidney disease have been produced after exposure to 
monocrotaline for 20 wk at a daily level of 80 Mg/kg 
(20). 

The toxicity of comfrey has been recently re- 
viewed (21). In rats, high levels of comfrey (0.5%- 
8% of the diet) are carcinogenic. The dangers to 
humans of low, chronic consumption are unknown. 
However, subacute exposure to the pyrrolizidine 
alkaloid monocrotaline produces toxic changes in 
rats that are only seen on acute dosing at higher 
levels (22). Our patient was consuming substances 
containing pyrrolizidine alkaloids on a daily basis, 
she had the symptoms of pyrrolizidine poisoning, 
and she showed structural changes in the liver 
characteristic of such poisoning. We believe, there- 
fore, that her condition was the result of prolonged 
consumption of low levels of pyrrolizidine alkaloid. 

Pyrrolizidine poisoning due to the use of herbal 
teas is being increasingly reported in the United 
States. Several cases have been found of children 
poisoned after being administered teas prepared 
from Senecio IongiJobus (3.4.23), and a case has been 
reported involving a woman using a CrotaJaria- 
containing tea (although identification of pyrrolizi- 
dine alkaloids was not made) (24). To our knowl- 
edge, this is the first report of venocclusive disease 
in any human after the use of a preparation claiming 
to be made from comfrey. 

References 

1. Mohabbat O. Shafig Younos M. Merzao AA. Strivastava RN. 
An outbreak of hepatic veno-occlusive disease in North- 
western Afghanistan. Lancet 1976:269-71. 

2. Tandon BN. Tandon RK. Tandon HD. Narndranathan M. Joshi 
YK. An epidemic of veno-occlusive disease of liver in Central 
India Lancet 1976:271-2. 

3. Stillman AE. Huxtable R. Consroe P. Kohnen P. Smith S. 
Hepatic \'eno-occlusive disease due to pyrrolizidine poison- 
ing in Arizona. Gastroenterology 1977.73 349-52. 

4. Fox DW. Hart MC. Bergeson PS. larrett PB. Stillman AE. 



364 



1054 RIDKER ET AL. 



GASTROENTEROLOGY Vol. 88. No. 4 



Huxtable R|. Pvrrolizidine (Senecio) intoxication mimicking 
Reyes syndrome. | Pediatr 1978:93:980-2. 

5. Cheeke PR. ed. Symposium on pyrrolizidine (Senecio) alka- 
loids: toxicity, metabolism, and poisonous plant control mea- 
sures. Oregon: Nutrition Research Institute, Oregon State 
University, Gorvallis, 1979. 

6. Dickinson |0. Cooke MP, King RR. Mohamed PA. Milk 
transfer of pyrrolizidine alkaloids in cattle. I Am Vet Med 
Assoc 1976:169:1192-6. 

7. Luthy J, Heim T. Schlatter C. Transfer of ( J H) pyrrolizidine 
alkaloids from Senecio vulgaris L. and metabolites into rat 
milk and tissues. Toxicol Lett 1983:17:283-8. 
Deinzer ML. Thomson PA. Burgett DM. Isaacson DL. Pyrroli- 
zidine alkaloids: their occurrence in honey from tansy rag- 
wort (Senecio jocobea L.). Science 1977:195:497-9. 
Culvenor CCF. Edgar (A. Smith LW. Pyrrolizidine alkaloids in 
honey from Echium plontogineum L- } Agric Food Chem 
1981:29:958-60. 

Furuya T. Hikichi M. Constituents of crude drugs: II. alka- 
loids and triterpenoids of Symphytum officinale. Phytochem- 
istry 1971:10:2217-20. 

Culvenor CCI. Clark M. Edgar |A. et al. Structure and toxicity 
of the alkaloids of Russian comfrey (Symphytum x uplandi- 
cum Nyman), a medicinal herb and item of human diet. 
Experientia 1980;36:377-9. 

Henry Doubleday Research Association. Announcement. Ob- 
server July 30. 1978. (Reported in Br Med I 1979:6163:598.) 

13. Huxtable R, Stillman A. Ciaramitaro D. Characterization of 



8 



9 



10 



11 



12 



16 



17 



alkaloids involved in human Senecio (pyrrolizidine) poison- 
ing. Proc West Pharmacol Soc 1977:20:455-9. 

14. Mattocks AR. Spectrophotometric determination of pyrrolizi- 
dine alkaloids — some improvements. AnaJ Chem 1968:40: 
1749-50. 

15. Willmot FC. Robertson GW. Senecio disease, or cirrhosis of 
the liver due to Senecio poisoning. Lancet 1920:848-9. 
Hill KR. Stafford JL. Aub R. Liver disease in Jamaican chil- 
dren (serous hepatosis). West Indian Med J 1951:1:49-63. 
Stuart KL. Bras G. Veno-occlusive disease of the liver. Q J 
Med 1957:26:291-315. 

18. Mattocks AR. Toxic pyrrolizidine alkaloids in comfrey. Lan- 
cet 1980 n 1136 

19. Roitman [N. Comfrey and liver damage. Lancet 1981;i:944. 

20. Hooper PT. Scanlan WA. Crotalana retusa poisoning of pigs 
and poultry. Aust Vet ) 1977:53:109-14. 
Anonymous. Comfrey. Lawrence Review of Natural Products 
1982:3:89-91. 

Huxtable R, Ciaramitaro D. Eisenstein D. The effects of a 
pyrrolizidine alkaloid, monocrotaline. and a pyrrole, dehy- 
droretronecine. on the biochemical functions of the pulmo- 
nary endothelium. Mol Pharmacol 1978:14:1189-1203. 

23. Huxtable RJ Herbal teas and toxins: novel aspects of pyrroli- 
zidine poisoning in the United States. Perspect Biol Med 
1980:24:1-14. 

24. Lydford CL. Vergara GG. Moeller DD. Hepatic veno-occlusive 
disease originating in Ecuador. Gastroenterology 1976; 
70:105-8. 



21 



22 



365 

Mr. Towns. Mr. McCaleb. 

STATEMENT OF ROBERT S. McCALEB, HERB RESEARCH 

FOUNDATION 

Mr. McCaleb. The Herb Research Foundation, which I rep- 
resent, is a nonprofit, tax exempt research and educational organi- 
zation which studies herbs and has a large library of scientific in- 
formation about them. 

Herbs and other dietary supplements are used by millions of 
Americans to improve health and prevent disease. This is a positive 
trend; people taking personal responsibility for their health and 
practicing self-care. 

We have, in this country, a health care cost crisis; and 37 million 
people have no insurance. Health care costs are our biggest cost of 
bankruptcy and industrial unrest. Two key factors in reducing 
these costs are prevention and self-care. I don't think there is any 
argument about that. 

In the absence of FDA-approved preventive medicines, dietary 
supplements are the substances healthy Americans take in order to 
improve their health and prevent disease. 

I will stress that 50 years of FDA regulation of drugs have failed 
to approve a single over-the-counter oral preventive medicine for 
the prevention of any major disease. We have no approved preven- 
tive medicines in this country. 

Herbs, as dietary supplements, offer the same benefits function- 
ally as vitamins and other substances in many cases. For example, 
antioxidants' cardiovascular disease protection, strengthening eye- 
sight — I noticed one of those products was on the counter here — 
and strengthening immunity. 

The FDA categorizes herbs as different because they are not nu- 
tritional. That means they are not essential nutrients. We have 
heard the characterization of acceptable attributes of food as flavor, 
or taste and aroma. We have a new concept in this country, and 
it is supported by a great deal of science supporting the use of 
foods as preventive health care agents; this includes broccoli as a 
cancer protective agent and many other benefits from herbs, in- 
cluding garlic which has some of those same properties. 

The FDA regulates these products as drugs and food additives in 
order to get them off the market. And we have had plenty of dis- 
cussion today of how inappropriate that is. The courts affirmed this 
recently, as you heard. 

You also asked, though, about the evidence that FDA still in- 
tends to do this. In my written testimony, there are quotes by Mi- 
chael Taylor, David Adams, and Bob Gilberts all suggesting that 
herbs should be regulated not only as drugs, but as new drugs and 
go through the $359 million process required for new drugs. 

The task force on dietary supplements recommends continuing to 
regulate herbs as food additives, despite the fact that it seems to 
be inappropriate, and is not what Congress intended by passing 
that act. 

The FDA's bias against these products is disturbing as they have 
carried a media campaign against them for 20 years continuing to 
this day. Current statements by FDA are misleading both to the 
public and Congress and raise serious ethical and legal questions 



366 

about a Federal agency carrying on a PR campaign against one of 
its regulated industries. 

In the dietary supplement task force, there is a surprising admis- 
sion by FDA that the agency wants to ensure that, "the existence 
of dietary supplements doesn't act as a disincentive for drug devel- 
opment.' 

In Europe, an extract of saw palmetto berries, which were used 
as staple food by Native Americans, is used in the treatment of be- 
nign prostatic hypertrophy. There are no known side effects. When 
it is used as a staple food, and it is half the cost of the drugs for 
sale and proven safer, why are we biased against it? 

I see I am out of time. I wanted to mention on the question of 
safety and effectiveness, our organization has proposed a mecha- 
nism for reviewing the safety of herbs as published in the Food and 
Drug Law Journal. 

Of the 400 major herbs on the market, 300 are already FDA ap- 
proved. We consider 25 of them already in reports like this by some 
scientists. We also recommended — and it is a pity Mr. Barrett is 
not still in the room — a proposal whereby industry sponsorship 
would be used for evaluating the claims. 

[The prepared statement of Mr. McCaleb follows:] 



367 



RATIONAL REGULATION OF HERBAL PRODUCTS 

TESTIMONY BEFORE THE SUBCOMMITTEE 

ON GOVERNMENT OPERATIONS 

Robert S. McCaleb 

Herb Research Foundation 

July 20, 1993 

INTRODUCTION 

This report describes the regulatory dilemma faced by herbal products, dietary supplements and 
medicinal plants. Our current regulatory system has virtually eliminated plants and their extracts 
from consideration as new drugs, and prevents known effects of foods and supplements from 
being disclosed to the public. After detailing the many reasons for changing the status quo, we 
present a proposed regulatory scheme for herbs. 

Herbal products, including herbal teas and dietary supplements are an industry of over one 
billion dollars in retail sales in the United States 1 . With the exception of a very few herbs which 
are approved for use as over-the-counter (OTC) drug ingredients, and isolated chemical 
compounds from plants in OTC and prescription medicine, most herbal products are regulated 
and sold as foods. According to the U.S. Food and Drug Administration, any product which is 
used for the prevention, treatment, mitigation or cure of any disease condition is considered a 
drug. Drug approval costs in the United States are extremely high, estimated at $359 million 
each according to the Chemical Marketing Reporter. Because botanicals are not patentable, they 
are not considered viable candidates for new drug approval, either by pharmaceutical companies 
or by herb companies, which lack the financial resources to even consider overcoming the 
regulatory obstacles. 

Because of this unfortunate situation, many safe and effective herbal dietary supplements and 
"phytomedicines" (plant-based drugs) cannot be sold in the U.S. or cannot be sold with proper 
directions for their use. There are many sound reasons for eliminating the barriers to natural 
remedies, and increasing their use as an integral part of American health care. The Herb 
Research Foundation believes that increased use of herbs as dietary supplements and plant 
medicines is one of our most productive options for improving public health while lowering 
health care costs. In other modem nations, medicinal plants serve as inexpensive alternatives to 
proprietary drugs for disease treatment, and especially as preventive medicines, a very neglected 
area in American health care. These remedies can become one of our most cost-effective and 
practical options for shifting the focus of modem health care from disease treatment to disease 
prevention and the promotion of wellness. Prevention and self-care are two of the keys to 
reducing health care costs. 

THE HEALTH CARE COST CRISIS 



Industry survey, American Herbal Products Association, 1991. 



368 

HRF Testimony: FDA Regulation of Dietary Supplements, page 2 



The American health care system is in a state of crisis. Over 37 million Americans cannot 
afford basic health insurance. As a percentage of gross national product, Americans pay twice as 
much as Europeans and three times as much as Japanese for health care costs, yet lag behind 
both groups in terms of measurable health statistics including longevity, infant mortality, cancer 
and heart disease rates. While the reasons for these excessive health care costs are complex, the 
direction and implications are clear. Every available option must be pursued to lower the cost 
of health care while maximizing the benefits. 

Here are some of the reasons why the cost of health care is such a compelling issue: 

"We spend over $600 billion a year on health care in the United States - more 
than $2,400 for every man, woman, and child in this country. Ironically for all 
the money we spend Americans are no healthier than people in many countries 
that spend considerably less than we do on health care; nor are we significantly 
healthier than we were 30 years ago when health care consumed only six percent 
oftheGNP. 

"America does not keep its people as healthy as our other industrial competitors: 
an American male is 15th in the world in life expectancy and American females 
are eighth; we are 20th in infant mortality; 12 nations have lower rates of cancer 
and 25 nations have better cardiovascular health. 

"Health care costs are the single biggest cause of bankruptcy and of industrial 
unrest." 

"Employer spending on health insurance has risen three times faster than wages 
since 1980. American businesses spent for health benefits more than they paid out 
in dividends." 2 

Because of these factors, there is a need for low cost alternatives to costly therapies wherever 
available. There is also an increasing consumer demand for natural alternatives and a wider 
range of choices in health care. Providing inexpensive self care options could help the U.S. to 
serve better the uninsured, and other segments of the population who are increasingly hard 
pressed to pay the skyrocketing costs of health care. 

AMERICAN DRUG APPROVAL COSTS 

Current FDA regulations have made new drug approval so expensive that non-patentable 
products, including herbs and other supplement ingredients, are not candidates for drug research 
and development. This is evident in the disturbing fact that no complex natural product has been 
approved for drug use since the 1962 amendments for drug efficacy testing were enacted. 
European and Asian countries have introduced hundreds of botanical remedies in this time 
period, some of which are now among the most widely used medicines in their health care 
systems. FDA has refused to treat complex natural remedies differently than potent new 



Lamm , Richard D. "The Brave New World of Health Care" Center for Public 
Policy and Contemporary Issues. University of Denver, May 1990 



369 

HRF Testimony: FDA Regulation of Dietary Supplements, page 3 



chemical synthetics, and failed to participate in the WHO process for developing their 
Guidelines For Traditional Medicines. 

The U.S. pharmaceutical industry and the medical community have grown accustomed to the 
current regulatory climate, and operate quite profitably within it. The medical community, 
which receives much of its education from the pharmaceutical industry, is largely unaware of the 
widespread use of medicinal plants in international health care. The insurance industry, too, is 
accustomed to the current system of health care and health care regulation. Drug companies, 
with their lucrative proprietary drugs, are unlikely to embrace the concept of increased use of 
non-patentable and lower-cost therapies. 

There is a tremendous disparity between the costs and time required to approve drugs in Europe 
and the U.S. The regulatory obstacles to development of natural remedies in the US must be 
eliminated, if we are to compete internationally in the health care market. It also makes sense to 
steer American drug development toward a wider diversity of potential new and old drugs, 
especially those which are non-proprietary and hence, less expensive. Phytomedicines can be 
used in preventive health care and self-care, both of which are acknowledged as lower-cost 
options than high-tech acute care and doctor-mediated prescription medicine. 

"U.S. approval of a new medicine take 8.5 years. European countries do it in 5 
years." 3 

ROLE OF DIETARY SUPPLEMENTS IN REDUCING HEALTH CARE COSTS 

As previously mentioned, the two key contributions which dietary supplements can make to 
health care are in the areas of prevention of disease and self care. 

PREVENTION 

The American health care system has been characterized as a "disease treatment system" because 
of the conspicuous absence of approved preventive medicines. Most dietary supplements are 
consumed in the belief that they will help to reduce the risk of disease. Research continues to 
document the potential utility of antioxidants, anticarcinogens, and other health-protective 
properties of herbs and other dietary supplements, which may reduce the risk of serious disease 
and could dramatically lower health care costs. Preventive medicine, frequently touted as a key 
to lowering health care costs is thwarted by FDA's current regulatory policies. 

In the U.S. we have no legitimate place in our regulatory framework for preventive medicines. 
After over 50 years of drug regulation, the FDA has not approved a single over-the-counter 
drug for internal use in the prevention of any major disease. The only non-prescription 
preventive medicines approved by FDA are fluoride toothpaste, sunscreen and motion sickness 
pills. During the 20 year process of "reviewing" OTC ingredients, FDA never even established a 
category in which preventive medicine products could be considered. We have a few 
prescription preventive drugs, such as those to treat hypertension and lower blood cholesterol, 
but these are available only to those with a pathological condition. Our only other preventive 
medicines, like vaccines and antimalarials, are also prescription only. 



Innovations in Medicine #17 Pharmaceutical Manufacturer's Association 



370 



HRF Testimony: FDA Regulation of Dietary Supplements, page 4 



European and Japanese consumers have access to dozens of government-approved natural 
remedies which have disease preventive effects. Among the best researched European 
phytomedicines, there are agents which can reduce the risk of all four of our leading natural 
causes of death: heart disease, cancer, respiratory disease and liver disease. The regulatory 
obstacles which have prevented research on medicinal plants constitute an even greater barrier to 
the approval of preventive medicines because these effects are harder to prove. Those countries 
which have access to such medicines have better longevity and less heart disease and cancer than 
the U.S. 

Dietary supplements are our preventive medicines. Healthy people take them in the belief that 
they can improve their health and reduce disease risk. Opinions differ about the value of 
supplements, and it may take years to sort out "the truth". In the meantime, supplements must be 
sold without disclosing what is already known about their effects. While the Nutrition Labeling 
and Education Act of 1990 (NLEA) might have offered some hope for a category of "preventive 
medicine" products within the food category, FDA's proposed regulations have largely dashed 
that hope. Their strict proposals are too drug-like, requiring levels of proof and petitioning 
procedures which are both unrealistic and unnecessary for food-safe supplements used as health- 
protective agents. Thus, under their proposal there is still no legitimate place for preventive 
medicines in America. 

CONTRIBUTIONS OF THE HEALTH-CONSCIOUS: The American health and fitness 
movement consists of a large and growing group of people who use diet, exercise and sometimes 
dietary supplements, to improve their health. This is the largest group of consumers who buy 
and use the products of the natural foods industry. They have made major contributions to the 
American diet, since many of the most healthful products now sold by grocers were first 
marketed in health food stores. These include such common items as whole grain breads, flours, 
cereals and pastas, yogurt, organic produce, herbal teas, coffee substitutes, and the whole range 
of reduced fat, sugar, salt, and preservative-free products, to mention just a few. 

Millions of these people are willing to spend their own resources on protecting their health 
through diet, exercise and supplements. They are not charging their herbs and vitamins to 
insurance companies or Medicaid. They are taking personal responsibility for their health care 
and attempting to practice preventive medicine, just as they should. Under the current 
regulatory system, this can be surprisingly hard to do. 

SELF CARE 

Speaking before the 1989 Conference on Self Care, Rep. Henry Waxman said, "A penny's worth 
of self care equals a dollar's worth of health care." This underscores Congress's recognition of 
self care as a cost-saving strategy, a strategy which is obstructed by FDA's rigid insistence on 
multimillion dollar approval mechanisms for non-patentable health-protective products. 

A recent Harvard survey concluded that over a third of Americans currently use alternative 
health care. Responsible self care requires an educated populace, and in opposing more 
informative labeling of health benefits and risks, FDA further inhibits this positive consumer 
trend. 



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There is also a trend in orthodox medicine toward self care, as prescription drugs are shifted into 
over-the-counter drug status, in recognition that the public does have the intelligence to self- 
medicate simple conditions. Current dietary supplements play an important role in self-care, and 
this role should be legitimized. 

FDA CURRENT REGULATION OF NATURAL PRODUCTS: 

Rational regulation of botanicals has eluded FDA, and the need for change is widely recognized. 
With the exception of a very few herbs which are approved for use as over-the-counter (OTC) 
drug ingredients, and isolated plant compounds in OTC and prescription medicine, most herbal 
products are regulated and sold as foods. According to the U.S. Food and Drug Administration, 
any product which is used for the prevention, treatment, mitigation or cure of any disease 
condition is considered a drug. 

DRUG STATUS : If any health claims are made or implied for an herbal product, FDA takes 
action against the product as an unapproved drug. This prevents manufacturers from disclosing 
known physiological effects of these products to the public, hampering their efforts at self care. 
This works against public health. 

FOOD ADDITIVE STATUS : FDA abuses food additive regulations to remove herbs from the 
market, claiming that the addition of water to an herb (as in the case of herbal teas) renders the 
herb a food additive. Addition of the herb to a gelatin capsule, FDA claims, also makes it a food 
additive. FDA's food additive laws were meant to protect consumers from synthetic chemicals 
added to food. Congress did not intend food additive legislation to regulate natural constituents 
of food itself. In fact, Congressman Delaney said in 1956, "There is hardly a food sold in the 
market today which has not had some chemicals used on or in it at some stage in its production, 
processing, packaging, transportation or storage." He stressed that his proposed bill was to 
assure the safety of "new chemicals that are being used in our daily food supply," and when 
asked if his bill applied to foods in general, Delaney said "just food additives only." 4 Foods 
which have a long history of safe use are exempted by law from the extensive laboratory tests 
required of new food chemicals, yet FDA has taken action under food additive regulations on 
numerous occasions against herbs with long histories of use. 

FDA'S PROPOSED REGULATIONS 

FDA's recently-released Dietary Supplement Task Force report proposes to perpetuate the 
misuse of food additive provisions. 5 The FDA proposed regulations for dietary supplements 
under NLEA retains language which would make health claims impossible for most 
supplements, and questions the lawfulness of many current dietary supplement ingredients. For 
example one section 6 appears to prevent the addition of any ingredient not essential to human 
nutrition, to vitamins, minerals, or to food labeled with nutritional claims. Presumably, herbs 



Federal Food, Drug, and Cosmetic Act (Chemical Additives in Food) : 

Hearings Before a Subcommittee of the Committee on Interstate and 

Foreign Commerce, 84th Cong., 2d Sess. 27 (1956). 

Dykstra, G. et al. FDA Dietary Supplement Task Force Final Report, June 

15, 1993. 

FDA proposed rules under NLEA, Section 101. 9 (k) 



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are considered among these "similar substances", and thus would be prohibited in many products 
labeled in accordance with the Act. We are unaware of any scientific or legal justification for 
this prohibition. There are numerous foods and dietary supplements which combine essential 
nutrients and other "ingredients or products" which are not essential nutrients. Such 
combinations are also protected by the Proxmire Amendment (Section 41 1 of the FD&C Act). 

NARROW DEFINITION OF FOODS EXCLUDES SUPPLEMENTS 

FDA proposes: 

"Consistent with the statute and applicable case law, FDA is proposing...that a 
substance that is the subject of a suggested claim that explains the advantages of 
consuming the substance at other than decreased levels must contribute taste, 
aroma or nutritional value to a food, or serve one or more of the technical effects 
listed in 21 CFR 170.3... Obviously a substance must be a food for it to have any 
significance in the diet... FDA is proposing... that the substance must retain its 
food attributes at the levels that are necessary to justify the claim." 

In this statement, FDA appears to be attempting to prevent health claims for any substance 
which is concentrated beyond that found in conventional foods. Further, with this proposal, the 
Agency seems to be requiring that foods or components thereof must retain their original 
attributes, including flavor and aroma, in order to qualify for a claim. This discriminates against 
dietary supplements in which such attributes are often intentionally eliminated. Consumers 
often use supplements primarily to concentrate the benefits of foods or reduce unwanted 
attributes. For example, they may take beta carotene supplements because they do not want to 
increase their consumption of carrots or other conventional sources, or want to consume a higher 
level than such foods offer. They may take garlic tablets for cardiovascular or cancer-protective 
benefits, while avoiding the flavor and aroma of garlic. In proposing that no claims be allowed 
for concentrated substances, and that they must retain "food attributes" like flavor and aroma, 
FDA seems to ignore the two very attributes that make supplements different from conventional 
foods. 

To be meaningful to supplements, regulations must permit undesired attributes of foods, eg. 
aroma, water or bulk, to be eliminated and benefits to be concentrated. 

FDA proposes: 

"If a claimed effect can only be achieved at a level of a vitamin mineral, or other 
substance that scientifically cannot be characterized as nutritional, but rather as 
therapeutic, then that fact will be considered by the agency in deciding whether 
the claim is appropriate for a food, or whether it is in fact a claim that would 
make the product a drug." 

"Under proposed section 101.14(b)(3)(i), food components that are modified to 
such an extent that they no longer retain their food attributes will also not be 
eligible to be the subject of a health claim. If claims are made for such 
components, the agency may well regard the components as drugs." 



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HRF Testimony: FDA Regulation of Dietary Supplements, page 7 



In these two statements, the agency underscores their reluctance to accept health claims for 
supplements, and threatens "concentrated" or "modified" substances with drug status. FDA 
knows, of course, that these unpatentable substances are not lucrative enough to be viable 
candidates for drug approval. 

SOME IMPACTS OF CURRENT REGULATION 

EFFECT ON T HE ELDERLY 

The populace of the United States is aging. Natural remedies as preventive health agents can 
help improve the health of the elderly and their quality of life; and can reduce the costs of acute 
care for diseases of the elderly, including cancer, pneumonia, heart disease, stroke and liver 
ailments. European consumers have access to well studied natural remedies and preventive 
medicines against our four leading causes of death (heart disease, cancer, respiratory and liver 
disease). Ironically, Americans are denied the use of these remedies because they are too 
inexpensive, that is, they are not sufficiently profitable to justify the cost of approval. FDA 
claims that their primary concern is safety, yet FDA-approved drugs have far more safety 
problems than herbal remedies used in Europe, Asia and elsewhere. The elderly in Europe and 
Asia also have access to natural remedies which are effective against common conditions of the 
elderly, including Ginkgo extracts against memory loss, vision problems and tinnitis, saw 
palmetto against prostatic hypertrophy, bilberry which prevents and treats diabetic retinopathy 
and others. Some of these are discussed later. These remedies, unlike FDA approved 
pharmaceuticals, are low in cost and have no known toxicity at recommended levels, even after 
use by tens of millions of patients. The record for drugs approved by FDA is far worse: 

"Adverse drug reactions put 243,000 older Americans in the hospital and cause 
dizziness or fainting spells in hundreds of thousands of others." 7 

"Within 15 years, Medicare outlays [for the elderly] will equal those for either 
Defense or Social Security. Only seven years after that, Medicare spending will 
equal that for Social Security and Defense combined. The money pit becomes a 
black hole that threatens to suck in the entire budget." 8 

MINORITY RIGHTS 

The American populace is becoming increasingly heterogeneous. Minority populations 
including African- American, Hispanic, Asian and others, are a growing part of every American 
city. These minority populations have a right to access to health care modalities and remedies 
which were available to them in their previous culture. Although not officially sanctioned, this 
is already the case with food and drug regulation in Oriental areas of major cities. Many 
minority populations have time-honored traditional medicine systems, which they and their 
ancestors have used successfully for centuries, and even millennia. FDA's refusal to allow such 
products to carry informative labeling does not further public health. For example, the Chinese 
medicinal plant dong quai has been safely used for thousands of years for uses discovered 



Kaufman et al. Over the Counter Pills that Don't Work Pantheon Books, 

New York, 1983. 

Richard D. Lamm, {op. cit.) 



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through careful observation. Once sold with indications which helped consumers to understand 
the uses and dosage of this herb, compliance with FDA rules has forced importers to relabel 
without any such indications. One such product, formerly called Dong quai tablets, are now 
called Angelica tea tablets. They can no longer give any indication of the traditional uses, nor 
the scientific facts about physiological effects of the plant. 

THE DECLINE OF LEGITIMATE RESEARCH ON PLANTS 

The regulatory lockout of natural remedies has not only impeded the herbal products industry, 
denied valuable remedies to the elderly and minorities, but has crippled natural products research 
in our Universities and hospitals. The fields of Pharmacognosy (the study of drugs of natural 
origin) and other academic pursuits involving the study of medicinal plants have declined 
alarmingly in the U.S. American scientists, once at the forefront of this type of research, are 
lagging behind their European and Japanese counterparts, further reducing the likelihood of 
American discoveries of useful new medicines from plants. This is of concern to the academics 
themselves and should be to policy makers concerned with international competitiveness. 

FDA BIAS 

FDA officials have recently begun pressing for application of the new drug application process 
to herbs and amino acids, knowing that there is no financial incentive for this. 

March 31, 1993 FDA's Michael Taylor, Deputy Commissioner for Policy, in a speech to 
the Federation of American Societies for Experimental Biology, declared that herbs and 
amino acids, unlike vitamins and minerals, are not nutritional and therefore are not foods. 
Taylor said they are "legally drugs and properly regulated as such." 

April 19, 1993 Dr. Robert Temple, FDA's Director of New Drugs, said that herbs should 
be approved by the same mechanism as new drugs. 

April 21, 1993 David Adams, Michael Taylor's Assistant, addressed scientists at a World 
Health Organization Symposium on traditional medicines, saying that herbs should be 
held to "the same standards" of safety and efficacy proof as "other drugs," and that FDA 
opposes any more lenient standard, which they would consider a "regulatory underclass 
of drugs." 

FDA MEDIA CAMPAIGN AGAINST HERBS 

FDA has made numerous misrepresentations about herbal products characterized by an alarming 
level of sensationalism. For example, in October 1983, FDA Consumer ran a cover story on 
herbs entitled "Danger - Herbs often more toxic than magical." 9 The cover illustration depicted 
a road sign in bright red with the words "Danger - Herbs" and a drawing of a skull and cross- 
bones rising from a cup of tea. The text of the article discussed the toxicity of 27 herbs with the 
implication that these were hazards that lurked in the health food store in the form of herbal teas. 
The list included such highly dangerous plants as foxglove, deadly nightshade and poison 
hemlock, which of course have never been promoted by the natural foods industry. More 



Larkin, T. Herbs are often more toxic than magical. FDA Consumer, 1983 
17 (8) :4-10. 



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recently, in May 1991, FDA Consumer produced another article about herbs. 10 The inside cover 
illustration depicted a foxglove leaf, a toxic plant which has never been used as an ingredient of 
herbal teas and is not available in health food stores. Facing the first page of the article is a 
cartoon showing a consumer clutching his stomach while drinking a cup of tea. Next to him on 
the counter is a cannister labeled "chamomile tea". The article describes an isolated incident of 
allergic reaction to chamomile and depicts herbs as unknown and potentially dangerous, as 
illustrated by the title, "Beware the unknown brew." Chamomile is a safe food ingredient, 
approved for use worldwide, including the U.S. Chamomile has been unfairly maligned. This 
herb is approved as a safe food ingredient in every country on earth. It is approved as safe by 
FDA, and is an ingredient in some of the most popular herbal teas in America. Chamomile is 
consumed at the rate of about one million cups per day. It is astonishing that FDA continues to 
attack an herb with a remarkably good safety record and which they themselves have approved 
as safe. 

Since FDA regulates herbs as "food additives", it is instructive to look at the Agencies reports of 
illness resulting from such ingredients. While FDA devotes cover stories to the so-called 
hazards of herbs, their own statistics show that herbs are not causing much of a problem. In fact, 
a 1988 FDA Consumer article, showed that 95% of consumer illness from "food additives" was 
caused by only two substances, aspartame (80%) and sulfites (15%)." 

Numerous other articles in the medical, scientific and popular press have perpetuated an 
apparently inaccurate portrayal of herbs as a public health menace. Searches by the Herb 
Research Foundation of information from the American Association of Poison Control Centers, 
National Library of Medicine's Medline Database, and other computer databases, failed to turn 
up a substantial number of serious toxicity incidents involving commercial herbal products. 

This inflammatory rhetoric by a public agency against one of their regulated industries raises 
disturbing questions, both ethical and legal. It amounts to a government- spionsored public 
relations campaign against an entire industry, and has confused the public, the medical and 
scientific communities, and legislators alike, as they collectively attempt to determine whether or 
not increased use of dietary supplements in modem health care is a sensible and rational option. 

CURRENT FDA MEDIA CAMPAIGN 

On May 24th through 26th, the CBS Evening News ran a series of three programs on the subject 
of dietary supplements. Similar programs have appeared on ABC News, local stations, and on 
morning shows like the Today Show and Good Morning America. The main themes of these 
programs were the assertions by FDA spokesmen and others that: 

1) herbs and other supplements are "virtually unregulated," 

2) that they may be unsafe, 

3) that the claims made for these products are not substantiated. 



10 Snider, S. Beware the unknown brew; herbal teas and toxicity. FDA 
Consumer, 1991 25 (4) :30-33 . 

11 Folkenberg, J. Reporting reactions to additives. FDA Consumer, 1988 
22(8) :16-17. 



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HRF Testimony: FDA Regulation of Dietary Supplements, page 10 



One of the most alarming features of the current media campaign against dietary supplements is 
the misrepresentation of the Food and Drug Administration's authority and responsibility in the 
regulation of dietary supplements. We do not believe the networks are a party to these 
misrepresentations, but rather are relying on the authority of presumed experts within the FDA, 
the Center for Science in the Public Interest (CSPI), and the National Organization for Rare 
Disorders (NORD). 

Based on information supplied by these organizations, the CBS correspondent repeatedly 
asserted that: 

"Dietary supplements are virtually unregulated by the government... Unlike foods 
in your grocery store or over-the-counter and prescription drugs in your 
pharmacy, dietary supplements are not required to conform to any legal standard 
of purity or potency." 

These statements and others, repeated often in the current media campaign, are simply not true. 
FDA's regular spokesperson on the various news programs is Michael Taylor, the Deputy 
Commissioner of FDA, in charge of policy. Mr. Taylor is an attorney, and as the Deputy 
Commissioner for Policy, is clearly aware of FDA's authority and responsibility under the law. 
His statements, according to a prominent food and drug attorney, were "wrong and misleading." 

Similarly FDA has both the authority and responsibility to remove any unsafe product from the 
market. Mr. Taylor's assertions to the contrary are false, misleading and alarmist. The fact is 
that FDA has failed to demonstrate in any way that supplements represent a serious health 
hazard and seems to be resorting to misleading publicity in its attempts to sway public and 
Congressional opinion. 

Dietary supplements are regulated as foods. Just as with all other foods: 

They are required to be safe. 

They must be manufactured according to the same standards of quality and sanitation as 
any other food. 

They are required to be accurately and adequately labeled in exactly the same way as 
other foods. 

They are required to conform to the legal standard for purity and potency just like 
medicines or other foods. 

In fact it is just as illegal for a vitamin product to contain less of the vitamin than is stated on the 
label as it is for a drug to contain less than its label claim. When FDA says this industry is 
unregulated, it is admitting its own failure in its responsibility to test vitamin products and take 
action against those which are sub-potent. There is no question that the supplement industry 
bears the primary responsibility to assure the potency and quality of its products, but Mr. Taylor 
was clear